Skip to main content

Advertisement

We're creating a new version of this page. See preview

  • Review
  • Open Access

Lipid metabolism reprogramming and its potential targets in cancer

Cancer Communications201838:27

https://doi.org/10.1186/s40880-018-0301-4

©  The Author(s) 2018

  • Received: 12 January 2018
  • Accepted: 12 May 2018
  • Published:

Abstract

Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy. Increased lipid uptake, storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. Lipids constitute the basic structure of membranes and also function as signaling molecules and energy sources. Sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors in the endoplasmic reticulum, play a central role in the regulation of lipid metabolism. Recent studies have revealed that SREBPs are highly up-regulated in various cancers and promote tumor growth. SREBP cleavage-activating protein is a key transporter in the trafficking and activation of SREBPs as well as a critical glucose sensor, thus linking glucose metabolism and de novo lipid synthesis. Targeting altered lipid metabolic pathways has become a promising anti-cancer strategy. This review summarizes recent progress in our understanding of lipid metabolism regulation in malignancy, and highlights potential molecular targets and their inhibitors for cancer treatment.

Keywords

  • Lipid metabolism
  • Cancer
  • SCAP
  • SREBPs
  • Fatty acids
  • Cholesterol
  • Lipid droplets

Background

Lipids, also known as fats, comprise thousands of different types of molecules, including phospholipids, fatty acids, triglycerides, sphingolipids, cholesterol, and cholesteryl esters. Lipids are widely distributed in cellular organelles and are critical components of all membranes [1–6]. In addition to their role as structural components, lipids in membranes also serve important functions of different organelles. Lipids could function as second messengers to transduce signals within cells, and serve as important energy sources when nutrients are limited [7–10]. Dysregulation of lipid metabolism contributes to the progression of various metabolic diseases, including cardiovascular diseases, obesity, hepatic steatosis, and diabetes [11–16].

Mammalian cells acquire lipids through two mechanisms, i.e., de novo synthesis and uptake. Accumulating evidence has demonstrated that lipid metabolism is substantially reprogrammed in cancers [17–22]. Lipogenesis is strongly up-regulated in human cancers to satisfy the demands of increased membrane biogenesis [7, 8, 21, 23]. Lipid uptake and storage are also elevated in malignant tumors [24–33]. Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that regulate the expression of genes involved in lipid synthesis and uptake, and play a central role in lipid metabolism under both physiological and pathological conditions (Fig. 1). Dysregulation of SREBPs occurs in various metabolic syndromes and cancers [34–46]. Targeting the pathways regulating lipid metabolism has become a novel anti-cancer strategy. In this review, we summarize the recent progress in lipid metabolic regulation in malignancies, and discuss molecular targets for novel cancer therapy.
Fig. 1
Fig. 1

Regulation of lipid metabolism in cancer cells. In cancer cells, glucose uptake and glycolysis are markedly up-regulated by RTKs via the PI3K/Akt/mTOR signaling pathway, generating large amounts of pyruvate. Pyruvate is converted to lactate and it also enters the mitochondria, where it forms citrate, which is transported by SLC25A1 from the mitochondria into the cytoplasm, where the citrate serves as a precursor for de novo synthesis of fatty acids and cholesterol. Glutamine can also enter into mitochondria and participate in energy production and lipid synthesis. Acetate is converted to acetyl-CoA by the ACSS2 enzyme, serving as another source of lipid synthesis. Glucose participates in the HBP to form glycans that will be added to proteins during glycosylation. Oncogenic EGFR signaling increases N-glycosylation of SCAP, which activates SREBP-1 and -2 [55, 58], which ultimately up-regulate expression of enzymes in lipogenesis pathways and expression of LDLR. The enzyme up-regulation promotes fatty acid and cholesterol synthesis, while the LDLR up-regulation increases cholesterol uptake [40]. The microRNA miRNA-29 regulates the SCAP/SREBP pathway via a novel negative feedback loop [101]. The transporter CD36 brings fatty acids into cancer cells. When cellular fatty acids and cholesterol are in excess, they can be converted to TG and CE by the enzymes DGAT1/2 and SOAT1/ACAT1, forming LDs. When present in excess, cholesterol can be converted to 22- or 27-hydroxycholesterol, which activate LXR to up-regulate ABCA1 expression, promoting cholesterol efflux. ABCA1 ATP-binding cassette transporters A, ACC acetyl-CoA carboxylase, ACLY ATP citrate lyase, ACSS2 acetyl-CoA synthetase 2, DGAT1/2 diacylglycerol O-acyltransferase 1/2, FAs fatty acids, FASN fatty acid synthase, HBP hexosamine biosynthesis pathway, HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCS 3-hydroxy-3-methylglutaryl-CoA synthase, LD lipid droplet, LDLR low-density lipoprotein receptor, LXR liver X receptor, RTKs oncogenic tyrosine kinase receptors, SCAP SREBP cleavage-activating protein, SCD1 stearoyl-CoA desaturase 1, SLC25A1 solute carrier family 25 member 1, SOAT1 (also known as ACAT1) sterol O-acyltransferase, SREBPs sterol regulatory element-binding proteins, TG/CE triglycerides/cholesteryl esters

Nutrient sources for lipid synthesis

Glucose is the major substrate for de novo lipid synthesis (Fig. 1). It is converted to pyruvate through glycolysis, and enters mitochondria to form citrate, which is then released into the cytoplasm to serve as a precursor for the synthesis of both fatty acids and cholesterol [47, 48]. Multiple glucose transporters as well as a series of enzymes that regulate glycolysis and lipid synthesis are strongly up-regulated in cancer cells [20, 21, 28, 49–54]. Glucose also participates in the hexosamine biosynthesis pathway to generate essential metabolites for the glycosylation of numerous proteins and lipids [55–57]. In this way, glycosylation is linked to the regulation of lipid metabolism [55, 58].

Glutamine could also be used for energy production and lipid synthesis via the tricarboxylic acid cycle in mitochondria [59–62]. Glutamine is the most abundant amino acid in the blood and tissues [63, 64]. It is a major nitrogen donor essential for tumor growth. Glutamine transporters, such as SLC1A5 (also known as ASCT2), are up-regulated in various cancers [65, 66]. After entering cells, glutamine can be converted to glutamate and α-ketoglutarate in the mitochondria, and generate ATP through oxidative phosphorylation [59–61, 67, 68]. Under conditions of hypoxia or defective mitochondria, glutamine-derived α-ketoglutarate is converted to citrate through reductive carboxylation and thereby contributes to de novo lipid synthesis [34, 69–71]. Acetate can also serve as a substrate for lipid synthesis after it is converted to acetyl-CoA in the cytoplasm [72–74].

De novo lipid synthesis

Key regulators of lipogenesis—SREBPs, acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1) [27, 75–81]—are significantly up-regulated in various human cancers [20, 21, 28, 49–51]. Below we detail the roles of these proteins and discuss their potential as molecular targets in cancer treatment.

SCAP/SREBPs

SREBPs are a family of basic-helix-loop-helix leucine zipper transcription factors that regulate de novo synthesis of fatty acids and cholesterol as well as cholesterol uptake [11, 12, 82]. Mammalian cells express three SREBP proteins, SREBP-1a, -1c and -2, which are encoded by two genes, SREBF1 and SREBF2. SREBF1 encodes SREBP-1a and -1c proteins via alternative transcriptional start sites. The SREBP-1a protein is ~ 24 amino acids longer than -1c at its NH2-terminus, and has stronger transcriptional activity. SREBP-1a regulates fatty acid and cholesterol synthesis as well as cholesterol uptake, whereas SREBP-1c mainly controls fatty acid synthesis [83–86]. SREBF2 encodes the SREBP-2 protein, and plays a major role in the regulation of cholesterol synthesis and uptake [87–92].

SREBPs are synthesized as inactive precursors that interact with SREBP cleavage-activating protein (SCAP), a polytopic transmembrane protein that binds to the insulin-induced gene protein (Insig), which is anchored to the endoplasmic reticulum (ER). The resulting Insig/SCAP/SREBP complex is retained in the ER [93–95]. Dissociation of SCAP from Insig, followed by a conformational change in SCAP, activates SREBP transcriptional activity. Conformational change in SCAP exposes a specific motif that allows SCAP to bind to Sec23/24 proteins, generating COPII-mediated translocation vesicles. SCAP mediates the entry of SREBPs into COPII vesicles that transport the SCAP/SREBP complex from the ER to the Golgi. In the Golgi, site 1 and 2 proteases (S1P and S2P) sequentially cleave SREBPs to release their N-terminal domains, which enter the nucleus and activate the transcription of genes involved in lipid synthesis and uptake (Fig. 1) [11, 12, 87, 88, 95, 96]. This process is negatively regulated by ER sterols, which are able to bind to SCAP or Insig and enhance their association, leading to the retention of SCAP/SREBP in the ER and reduction of SREBP activation [97–100]. Our research group recently showed that microRNA-29 (miR-29) participates in the negative feedback control of the SCAP/SREBP signaling pathway. We found that SREBP-1 up-regulates miR-29 transcription, and the microRNA binds to the 3′-untranslated region of SCAP and SREBP-1 transcripts and inhibit their translation [101, 102].

SCAP N-glycosylation

A recent series of studies in our laboratory showed that glucose could activate SCAP/SREBP trafficking and activation (Fig. 2) [55, 103, 104]. We tested the effects of glucose intermediate metabolites on different metabolic pathways, including glycolysis, oxidative phosphorylation, and hexosamine synthesis for glycosylation. We found that only N-acetylglucosamine (GlcNAc), an intermediate in the hexosamine biosynthesis pathway, activates SREBPs when glucose supply is limited. We found that inhibiting N-glycosylation, but not O-glycosylation, abolished glucose-mediated SCAP up-regulation and SREBP activation, indicating that glucose-mediated N-glycosylation of SCAP is essential for SCAP/SREBP trafficking and activation. These findings also demonstrated a coordinated molecular regulation mechanism that links glucose availability and the rate of de novo lipid synthesis (Fig. 2) [55, 58, 105].
Fig. 2
Fig. 2

SCAP N-glycosylation is essential for SREBP trafficking and activation. SREBP activation is repressed by the ER-resident protein Insig, which binds to SCAP to prevent SREBP translocation and nuclear activation. The Nobel Prize-winning laboratories of Brown and Goldstein revealed that sterols modulate Insig interaction with SCAP to retain the SCAP/SREBP complex in the ER and inhibit SREBP [273, 274]. Our recent work has shown that glucose-mediated N-glycosylation stabilizes SCAP and promotes its dissociation from Insig, triggering the trafficking of the SCAP/SREBP complex from the ER to the Golgi, where SREBPs are cleaved to release their transcriptionally active N-terminal fragments to activate lipogenesis for tumor growth [55]. We further showed that EGFR signaling enhances glucose intake and thereby promotes SCAP N-glycosylation and SREBP activation

SREBP activation in malignancy

The importance of SREBPs in cancer has begun to be recognized. Our group discovered that SREBP-1 is markedly up-regulated in glioblastoma [34, 106–108], the most common primary brain tumor and one of the most lethal cancers [34, 109–113]. Glioblastomas depend strongly on lipogenesis for rapid growth when they express the amplified tyrosine kinase receptor called epidermal growth factor receptor (EGFR) or its constitutively active mutant form EGFRvIII. This mutant lacks a portion of the extracellular ligand-binding domain [34, 106, 108, 111, 114, 115]. EGFR/EGFRvIII promotes lipid synthesis by activating SREBP-1 via PI3K/Akt signaling [12, 34, 87]. The nuclei of human glioblastoma cells display elevated levels of SREBP-1 [34], suggesting that the SCAP/SREBP complex may escape the tight repression of Insig, leading to high SREBP activation. Other groups have found elevated SREBP-1 in various cancers, and SREBP-1 levels in various cell lines are regulated by PI3K/Akt signaling and mTORC1 [116–122]. How SREBP-1 is activated in cancer cells is not entirely understood and requires further investigation.

Inhibiting SREBPs at the genetic level or with pharmacological agents significantly suppresses tumor growth and induces cancer cell death, making SREBPs promising therapeutic targets [28, 34, 123–137]. However, directly inhibiting SREBPs is challenging, as transcription factors often make poor drug targets. A more promising approach is to inhibit SREBP translocation from the ER to the Golgi. Along this line, fatostatin, betulin and PF-429242 have been shown to inhibit SREBP activation and have promising anti-tumor effects in pre-clinical studies [126–131].

SREBP-2 is up-regulated in prostate cancer [37, 138]. SREBP-2 regulates 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol synthesis. Inhibiting SREBP-2 has been explored as an anti-cancer therapy [139–144]. Statins are inhibitors of HMG-CoA reductase and are widely used to reduce circulating cholesterol levels. The anti-cancer effects of statins have been tested for various types of cancers, both pre-clinically and in patients [140, 142, 143, 145]. However, inhibition of cholesterol synthesis can lead to feedback activation of SREBPs, making the anti-cancer effects of statins less effective [144]. Thus, combination therapies that simultaneously inhibit cholesterol synthesis and SREBP activation are being developed [146, 147].

SLC25A1

A critical step for glucose-mediated de novo lipid synthesis is the release of citrate from mitochondria into the cytoplasm. Solute carrier family 25 member 1 (SLC25A1), also referred to as citrate carrier (CIC), functions as a key transporter to export citrate from mitochondria to the cytoplasm, providing a key precursor for both fatty acid and cholesterol synthesis [148, 149] (Fig. 1). SLC25A1 is regulated by SREBP-1 [150] and plays an important role in inflammation and tumor growth [151, 152]. In lung cancer cells, SLC25A1 is up-regulated by mutant p53 [151]. These findings, though preliminary, suggest that specific inhibitors of SLC25A1 may have anti-tumor effects.

ACLY

ATP citrate lyase (ACLY) converts cytoplasmic citrate to acetyl-CoA, a precursor of lipid synthesis (Fig. 1) [153–155] and a substrate for protein acetylation [153]. ACLY is a downstream target of SREBPs [156–158], and is up-regulated in many cancers, including glioblastoma, colorectal cancer, breast cancer, non-small cell lung cancer, and hepatocellular carcinoma [159–161]. Inhibiting ACLY at the genetic level or pharmacologically significantly suppresses tumor growth [162–164]. The ACLY inhibitor SB-204990 strongly inhibits tumor growth in mice with lung, prostate or ovarian cancer xenografts [162, 165]. These results suggest that ACLY may serve as an attractive anti-cancer target [155].

ACSS2

Acetate is converted to acetyl-CoA by acetyl-CoA synthetases (ACSSs), making acetate an important molecule for lipid synthesis and histone acetylation [7]. In mammalian cells, ACSS isoforms 1 and 3 localize to the mitochondria, whereas isoform 2 is found in the cytoplasm and nucleus [166]. Isoform 2 expression is regulated by SREBPs [167]. When each isoform was genetically knocked down in HepG2 cells, only ACSS2 down-regulation dramatically suppressed acetate-mediated lipid synthesis and histone modification [72]. In fact, ACSS2 expression correlates inversely with overall survival in patients with triple-negative breast cancer, liver cancer, glioma or lung cancer [72, 73, 168, 169]. Studies with patient-derived glioblastoma xenografts have shown that acetate contributes to acetyl-CoA synthesis in tumors [73]. Indeed, cancer cells rely mainly on acetate as a carbon source for fatty acid synthesis under hypoxic conditions [74]. Knocking down ACSS2 suppresses proliferation of several cancer cell lines as well as growth of xenograft tumors [74, 170–173]. ACSS2 also participates in autophagy when glucose supply is limited: it triggers histone acetylation in the promoter regions of autophagy genes, enhancing their expression [174, 175].

ACCs

Following the conversion of citrate and acetate to acetyl-CoA, the ACC enzymes catalyze ATP-dependent carboxylation of acetyl-CoA, generating malonyl-CoA for fatty acid synthesis (Fig. 1). Two ACC isoforms have been identified in mammalian cells, ACC-alpha (also termed ACC1) and ACC-beta (also known as ACC2) [176, 177]. ACC is up-regulated in several human cancers, including glioblastoma and head and neck squamous cell carcinoma [34, 178]. Inhibiting ACCs significantly reduces fatty acid synthesis and suppresses tumor growth in various xenograft models [179–186]. The ACC inhibitors TOFA, soraphen A and ND646 have shown significant anti-tumor effects in xenograft tumor models (Table 1) [179–184].
Table 1

Representative targets within the lipid metabolism pathway for anti-cancer drug development

Target protein

Inhibitor

Type of cancer

Preclinical model

Clinical trial

References

SCAP

–

GBM

Xenografts

–

[55]

SREBPs

Fatostatin, betulin, PF-429242, xanthohumol

GBM, prostate, liver, skin, melanoma, colorectal, bile duct, pancreatic, and breast cancer

Xenografts

–

[28, 125–138]

ACCs

TOFA, soraphen A, ND-646

Lung, ovarian cancer, head and neck squamous cell carcinoma

Xenografts

–

[179–185]

ACLY

SB-204990, bempedoic acid, BMS303141

Lung, prostate, and ovarian cancer

Xenografts

–

[152, 162, 165]

FASN

Cerulenin

Ovarian cancer, breast cancer

Xenografts

–

[179, 194–196]

 

C75

Breast, GBM, renal, and mesothelioma cancer

Xenografts

–

[34, 179, 188, 197–203]

 

TVB-2640

Solid malignant tumors

–

Phase I

Clinicaltrials.gov (NCT02223247), [191]

 

TVB-3166

Lung, ovary, and pancreatic cancer

Xenografts

–

[264]

 

C93

Ovarian and lung cancer

Xenografts

–

[265, 266]

 

C247

Breast cancer

 

–

[267]

 

Orlistat

Prostate cancer and melanoma

Xenografts

–

[192, 193]

 

Triclosan

Breast cancer

Xenografts

–

[268, 269]

LDLR

–

GBM

–

–

[27, 219]

SCD1

BZ36, A939572, MF-438

Prostate, renal cancer

Xenografts

–

[124, 212–215, 270]

LXR

GW3965, LXR-623

GBM

Xenografts

–

[27, 238, 239]

 

SR9243

Prostate cancer

Xenografts

 

[242]

SOAT1 (or ACAT1)

K604, ATR-101, avasimibe

GBM, prostate and pancreatic cancer

Xenografts

–

[28, 230–232]

CPT1

Etomoxir, perhexiline

Leukemia, prostate and breast cancer

Xenografts, transgenic mice

–

[248–250, 271, 272]

CD36

Anti-CD36 antibodies

Oral cancer

Xenografts

–

[24–26]

ACCs acetyl-CoA carboxylases, ACLY ATP citrate lyase, CD36 cluster of differentiation 36, also known as fatty acid translocase (FAT), CPT1 carnitine palmitoyltransferase 1, FASN fatty acid synthase, GBM glioblastoma multiforme, LDLR low-density lipoprotein receptor, LXR liver X receptor, SCAP SREBP cleavage-activating protein, SREBPs sterol regulatory element-binding proteins

FASN

Fatty acid synthase (FASN), a key lipogenic enzyme catalyzing the last step in de novo biogenesis of fatty acids, has been studied extensively in various cancers [21, 187–191]. The early-generation FASN inhibitors C75, cerulenin and orlistat (Table 1) have been studied pre-clinically, but their pharmacology and side effects limited their potential for clinical use [34, 179, 188–203]. The later-generation inhibitor TVB-2640 has entered clinical trials in patients with solid tumors (Table 1) [21, 191, 204, 205].

SCD1

Stearoyl-CoA desaturase (SCD) is an ER-resident integral membrane protein that catalyzes the formation of the mono-unsaturated fatty acids oleic acid (18:1) or palmitoleic acid (16:1) from stearoyl-(18:0) or palmitoyl-CoA (16:0) [206, 207]. There are 5 SCD genes (SCD1-5). Humans contain the SCD homologs SCD1 and SCD5, but the function of SCD5 remains unknown [208–210]. The mono-unsaturated products of SCD1 are key substrates in the formation of membrane phospholipids, cholesteryl esters and triglycerides, making SCD1 a promising anti-cancer target [75, 211]. The SCD1 inhibitors BZ36, A939572 and MF-438 have shown anti-tumor effects in pre-clinical xenograft models (Table 1) [212–215].

Lipid uptake

CD36

In addition to de novo synthesis, lipid uptake from the exogenous environment is another important route through which cells acquire fatty acids. CD36 transports fatty acids into the cell [216, 217], and plays a critical role in cancer cell growth, metastasis and the epithelial-mesenchymal transition [24–26]. An anti-CD36 antibody has shown significant anti-metastatic efficacy in oral cancer xenograft models [25].

LDLR

Cholesterol is an essential structural component of cell membranes [2, 218]. Cholesterol could be synthesized by cells de novo or through internalizing low-density lipoprotein (LDL). LDL binds to the membrane-bound LDL receptor (LDLR) and is internalized, after which it enters lysosomes, where free cholesterol is released [11, 76]. LDLR is up-regulated in glioblastoma via EGFR/PI3K/Akt/SREBP-1 signaling [27], and plays an important role in tumor growth [27, 76, 219]. LDLR has not been investigated as an anti-cancer target.

Lipid storage/lipid droplets

SOAT1/ACAT1

When cellular lipids are in excess, they are converted to triglycerides and cholesteryl esters in the ER, forming lipid droplets [220–222]. These droplets have been observed in various types of tumor, including glioblastoma, renal clear cell carcinoma, and cancers of the prostate, colon or pancreas [29–33]. Diglyceride acyltransferase 1/2 (DGAT1/2) could synthesize triglyceride from diacylglycerol and acyl-CoA (Fig. 1) [223, 224]. So far, the role of triglycerides in cancer cells has not been explored.

Cholesteryl esters are abundant in tumor tissue, while they are usually undetectable in normal tissue [225–229]. Sterol O-acyltransferase 1 (SOAT1), also known as acyl-CoA acyltransferase 1 (ACAT1), converts cholesterol to cholesteryl esters for storage in lipid droplets (Fig. 1). This enzyme is highly expressed in glioblastomas and in cancer of the prostate or pancreas; its expression level correlates inversely with patient survival [28, 29, 230–235]. Genetically silencing SOAT1/ACAT1 or blocking its activity using the inhibitors K604, ATR-101 or avasimibe effectively suppresses tumor growth in several cancer xenograft models [28, 230–232]. These results suggest that targeting SOAT1 and cholesteryl ester synthesis may be a promising anti-cancer strategy.

Cholesterol efflux

LXR/ABCA1

Cholesterol homeostasis is critical for maintaining cellular function, and is regulated by de novo synthesis, uptake, storage, and efflux [11, 76]. Increases in cholesterol levels can trigger feedback inhibition of cholesterol biosynthesis or conversion of cholesterol into cholesteryl esters stored in lipid droplets. Levels of 22- or 27-hydroxycholesterol can also increase, and these molecules bind to and activate the liver X receptor, which turns on expression of ATP-binding cassette proteins A1 (ABCA1) and G1 (ABCG1) [236]. Both proteins are plasma membrane-bound transporters that promote cholesterol export and thereby reduce intracellular cholesterol levels [237]. Synthetic liver X receptor agonists GW3965 and T0901317 significantly inhibit tumor growth in animal models of glioblastoma, breast cancer or prostate cancer [7, 27]. Activation of the liver X receptor by GW3965 up-regulates a ubiquitin ligase E3 that degrades LDLR [27, 62, 238]. The highly brain-penetrant liver X receptor agonist LXR-623 selectively kills glioblastoma cells and prolongs survival of glioblastoma-bearing mice [239]. Therefore, the combination of increasing cholesterol efflux by activating the liver X receptor and decreasing cholesterol uptake may be a promising anti-cancer strategy.

Activation of liver X receptor up-regulates transcription of glycolysis genes, such as those encoding PFK2 and GCK1, as well as of lipogenesis genes, such as those encoding SREBP-1c, FASN, and SCD [240, 241]. Conversely, inhibiting the liver X receptor using the inverse agonist SR9243 downregulates expression of PFK2 and SREBP-1c, thereby inhibiting glycolysis and fatty acid synthesis as well as suppressing xenograft tumor growth [242]. These results suggest that developing antagonists against liver X receptors may be a new anti-cancer direction. However, such an approach can be effective only if the liver X receptor shows high transcriptional activity in human tumors, which has not been clearly demonstrated yet. Moreover, inhibiting liver X receptors alone may be insufficient for reducing glycolysis and lipogenesis in human tumors, since these metabolic programs are up-regulated by multiple oncogenic signaling pathways [243–245]. Regardless, efforts to inhibit cancer growth by using liver X receptor agonists to activate cholesterol efflux can be undermined by the concomitant up-regulation of glycolysis and lipogenesis. It may be more effective to simultaneously enhance cholesterol efflux and inhibit glycolysis and lipogenesis.

Fatty acid oxidation

CPT1

Fatty acids are an important energy source for cell growth and survival when nutrients are limiting. Carnitine palmitoyltransferase I (CPT1) converts fatty acids to acylcarnitines, which are shuttled into mitochondria, where they undergo β-oxidation and produce energy [21]. Fatty acid β-oxidation plays a critical role in tumor growth [246, 247], and the CPT1 inhibitors etomoxir and perhexiline have been tested for anti-cancer effects in various animal models [248–250].

Lipid peroxidation and cell death

Lipids, particularly polyunsaturated fatty acids, are susceptible to oxidation by oxygen free radicals, leading to lipid peroxidation that is harmful to cells and tissues [251–253]. Lipid peroxides are associated with many pathological states, including inflammation, neurodegenerative disease, cancer, and ocular and kidney degeneration [253, 254]. Lipid peroxidation triggers the propagation of lipid reactive oxygen species that can significantly alter the physical properties of cellular membranes, or degrade into reactive compounds that cross-link DNA or proteins, exerting further toxic effects [253, 255, 256]. Extensive lipid peroxidation can result in ferroptosis, a regulated form of iron-dependent, non-apoptotic cell death [255, 257]. Inducing ferroptosis may be an anti-cancer strategy [257–259]. For example, disrupting the repair of oxidative damage to bio-membranes by inhibiting the antioxidant enzyme glutathione peroxidase 4 (GPX4) could induce ferroptosis [257, 259–262]. This has emerged as an active area of research that may lead to new anti-cancer approaches, particularly against metabolically active tumors.

Summary

Extensive studies have provided strong evidence for reprogramming of lipid metabolism in cancer [27, 34, 55]. A variety of lipid synthesis inhibitors have shown promising anti-cancer effects in preclinical studies and early phases of clinical trials [7, 29, 55, 263]. However, major barriers exists in developing cancer treatment by targeting altered lipid metabolism, mostly due to incomplete understanding of the mechanisms that regulate lipid synthesis, storage, utilization and efflux in cancer cells.

Declarations

Authors’ contributions

CC performed the literature search and drafted the manuscript. FG and XC assisted in the literature search and helped draft sections of the manuscript. DG designed and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors wish to thank Dr. Martine Torres for critical review of the manuscript and editorial assistance.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

The data supporting the conclusions of this article are included within the article and Table 1.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Funding

This work was supported by NIH Grant NS079701 (DG), American Cancer Society Research Scholar Grant RSG-14-228-01-CSM (DG), OSUCCC Idea Grant (DG), an OSUCCC Translational Therapeutic Program seed grant (DG), a Pelotonia Postdoc Fellowship (CC) and an OSU Department of Radiation-Oncology Basic Research seed Grant (CC).

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Columbus, OH 43210, USA

References

  1. Maxfield FR. Plasma membrane microdomains. Curr Opin Cell Biol. 2002;14(4):483–7.PubMedView ArticleGoogle Scholar
  2. Mukherjee S, Maxfield FR. Membrane domains. Annu Rev Cell Dev Biol. 2004;20:839–66. https://doi.org/10.1146/annurev.cellbio.20.010403.095451.PubMedView ArticleGoogle Scholar
  3. Pomorski T, Hrafnsdottir S, Devaux PF, van Meer G. Lipid distribution and transport across cellular membranes. Semin Cell Dev Biol. 2001;12(2):139–48. https://doi.org/10.1006/scdb.2000.0231.PubMedView ArticleGoogle Scholar
  4. van Meer G. Membranes in motion. EMBO Rep. 2010;11(5):331–3. https://doi.org/10.1038/embor.2010.60.PubMedPubMed CentralView ArticleGoogle Scholar
  5. van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9(2):112–24. https://doi.org/10.1038/nrm2330.PubMedPubMed CentralView ArticleGoogle Scholar
  6. Holthuis JC, Menon AK. Lipid landscapes and pipelines in membrane homeostasis. Nature. 2014;510(7503):48–57. https://doi.org/10.1038/nature13474.PubMedView ArticleGoogle Scholar
  7. Guo D, Bell EH, Chakravarti A. Lipid metabolism emerges as a promising target for malignant glioma therapy. CNS Oncol. 2013;2(3):289–99. https://doi.org/10.2217/cns.13.20.PubMedPubMed CentralView ArticleGoogle Scholar
  8. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7(10):763–77. https://doi.org/10.1038/nrc2222.PubMedView ArticleGoogle Scholar
  9. Zechner R, Strauss JG, Haemmerle G, Lass A, Zimmermann R. Lipolysis: pathway under construction. Curr Opin Lipidol. 2005;16(3):333–40.PubMedView ArticleGoogle Scholar
  10. Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature. 2015;517(7534):302–10. https://doi.org/10.1038/nature14190.PubMedPubMed CentralView ArticleGoogle Scholar
  11. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell. 2015;161(1):161–72. https://doi.org/10.1016/j.cell.2015.01.036.PubMedPubMed CentralView ArticleGoogle Scholar
  12. Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell. 2006;124(1):35–46. https://doi.org/10.1016/j.cell.2005.12.022.PubMedView ArticleGoogle Scholar
  13. Schwartz MW, Seeley RJ, Tschop MH, Woods SC, Morton GJ, Myers MG, et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature. 2013;503(7474):59–66. https://doi.org/10.1038/nature12709.PubMedPubMed CentralView ArticleGoogle Scholar
  14. Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156(1–2):20–44. https://doi.org/10.1016/j.cell.2013.12.012.PubMedPubMed CentralView ArticleGoogle Scholar
  15. Perry RJ, Samuel VT, Petersen KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature. 2014;510(7503):84–91. https://doi.org/10.1038/nature13478.PubMedPubMed CentralView ArticleGoogle Scholar
  16. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332(6037):1519–23. https://doi.org/10.1126/science.1204265.PubMedPubMed CentralView ArticleGoogle Scholar
  17. Abramson HN. The lipogenesis pathway as a cancer target. J Med Chem. 2011;54(16):5615–38. https://doi.org/10.1021/jm2005805.PubMedView ArticleGoogle Scholar
  18. Grossi-Paoletti E, Paoletti P, Fumagalli R. Lipids in brain tumors. J Neurosurg. 1971;34(3):454–5. https://doi.org/10.3171/jns.1971.34.3.0454.PubMedView ArticleGoogle Scholar
  19. Podo F. Tumour phospholipid metabolism. NMR Biomed. 1999;12(7):413–39.PubMedView ArticleGoogle Scholar
  20. Santos CR, Schulze A. Lipid metabolism in cancer. FEBS J. 2012;279(15):2610–23. https://doi.org/10.1111/j.1742-4658.2012.08644.x.PubMedView ArticleGoogle Scholar
  21. Rohrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16(11):732–49. https://doi.org/10.1038/nrc.2016.89.PubMedView ArticleGoogle Scholar
  22. Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491(7424):364–73. https://doi.org/10.1038/nature11706.PubMedView ArticleGoogle Scholar
  23. Yoon S, Lee MY, Park SW, Moon JS, Koh YK, Ahn YH, et al. Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J Biol Chem. 2007;282(36):26122–31. https://doi.org/10.1074/jbc.M702854200.PubMedView ArticleGoogle Scholar
  24. Zhao J, Zhi Z, Wang C, Xing H, Song G, Yu X, et al. Exogenous lipids promote the growth of breast cancer cells via CD36. Oncol Rep. 2017;38(4):2105–15. https://doi.org/10.3892/or.2017.5864.PubMedPubMed CentralView ArticleGoogle Scholar
  25. Pascual G, Avgustinova A, Mejetta S, Martin M, Castellanos A, Attolini CS, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature. 2017;541(7635):41–5. https://doi.org/10.1038/nature20791.PubMedView ArticleGoogle Scholar
  26. Nath A, Li I, Roberts LR, Chan C. Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci Rep. 2015;5:14752. https://doi.org/10.1038/srep14752.PubMedPubMed CentralView ArticleGoogle Scholar
  27. Guo D, Reinitz F, Youssef M, Hong C, Nathanson D, Akhavan D, et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 2011;1(5):442–56. https://doi.org/10.1158/2159-8290.CD-11-0102.PubMedPubMed CentralView ArticleGoogle Scholar
  28. Geng F, Cheng X, Wu X, Yoo JY, Cheng C, Guo JY, et al. Inhibition of SOAT1 suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis. Clin Cancer Res. 2016;22(21):5337–48. https://doi.org/10.1158/1078-0432.CCR-15-2973.PubMedPubMed CentralView ArticleGoogle Scholar
  29. Geng F, Guo D. Lipid droplets, potential biomarker and metabolic target in glioblastoma. Intern Med Rev (Washington, DC). 2017. https://doi.org/10.18103/imr.v3i5.443.View ArticleGoogle Scholar
  30. Koizume S, Miyagi Y. Lipid Droplets: a key cellular organelle associated with cancer cell survival under normoxia and hypoxia. Int J Mol Sci. 2016. https://doi.org/10.3390/ijms17091430.PubMedPubMed CentralView ArticleGoogle Scholar
  31. Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3 K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 2014;19(3):393–406. https://doi.org/10.1016/j.cmet.2014.01.019.PubMedPubMed CentralView ArticleGoogle Scholar
  32. Accioly MT, Pacheco P, Maya-Monteiro CM, Carrossini N, Robbs BK, Oliveira SS, et al. Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells. Cancer Res. 2008;68(6):1732–40. https://doi.org/10.1158/0008-5472.CAN-07-1999.PubMedView ArticleGoogle Scholar
  33. Gaida MM, Mayer C, Dapunt U, Stegmaier S, Schirmacher P, Wabnitz GH, et al. Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule. Oncotarget. 2016;7(11):12623–32. https://doi.org/10.18632/oncotarget.7206.PubMedPubMed CentralView ArticleGoogle Scholar
  34. Guo D, Prins RM, Dang J, Kuga D, Iwanami A, Soto H, et al. EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci Signal. 2009;2(101):ra82. https://doi.org/10.1126/scisignal.2000446.PubMedPubMed CentralView ArticleGoogle Scholar
  35. Jeon TI, Osborne TF. SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol Metab. 2012;23(2):65–72. https://doi.org/10.1016/j.tem.2011.10.004.PubMedView ArticleGoogle Scholar
  36. Shao W, Espenshade PJ. Expanding roles for SREBP in metabolism. Cell Metab. 2012;16(4):414–9. https://doi.org/10.1016/j.cmet.2012.09.002.PubMedPubMed CentralView ArticleGoogle Scholar
  37. Ettinger SL, Sobel R, Whitmore TG, Akbari M, Bradley DR, Gleave ME, et al. Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen independence. Cancer Res. 2004;64(6):2212–21.PubMedView ArticleGoogle Scholar
  38. Yang Y, Morin PJ, Han WF, Chen T, Bornman DM, Gabrielson EW, et al. Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c. Exp Cell Res. 2003;282(2):132–7.PubMedView ArticleGoogle Scholar
  39. Bao J, Zhu L, Zhu Q, Su J, Liu M, Huang W. SREBP-1 is an independent prognostic marker and promotes invasion and migration in breast cancer. Oncol Lett. 2016;12(4):2409–16. https://doi.org/10.3892/ol.2016.4988.PubMedPubMed CentralView ArticleGoogle Scholar
  40. Huang WC, Li X, Liu J, Lin J, Chung LW. Activation of androgen receptor, lipogenesis, and oxidative stress converged by SREBP-1 is responsible for regulating growth and progression of prostate cancer cells. Mol Cancer Res. 2012;10(1):133–42. https://doi.org/10.1158/1541-7786.MCR-11-0206.PubMedView ArticleGoogle Scholar
  41. Yin F, Sharen G, Yuan F, Peng Y, Chen R, Zhou X, et al. TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway. Oncogenesis. 2017;6(6):e347. https://doi.org/10.1038/oncsis.2017.49.PubMedPubMed CentralView ArticleGoogle Scholar
  42. Sun Y, He W, Luo M, Zhou Y, Chang G, Ren W, et al. SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting lipid metabolism. Tumour Biol. 2015;36(6):4133–41. https://doi.org/10.1007/s13277-015-3047-5.PubMedView ArticleGoogle Scholar
  43. Li C, Yang W, Zhang J, Zheng X, Yao Y, Tu K, et al. SREBP-1 has a prognostic role and contributes to invasion and metastasis in human hepatocellular carcinoma. Int J Mol Sci. 2014;15(5):7124–38. https://doi.org/10.3390/ijms15057124.PubMedPubMed CentralView ArticleGoogle Scholar
  44. Walker AK, Jacobs RL, Watts JL, Rottiers V, Jiang K, Finnegan DM, et al. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell. 2011;147(4):840–52. https://doi.org/10.1016/j.cell.2011.09.045.PubMedPubMed CentralView ArticleGoogle Scholar
  45. Soyal SM, Nofziger C, Dossena S, Paulmichl M, Patsch W. Targeting SREBPs for treatment of the metabolic syndrome. Trends Pharmacol Sci. 2015;36(6):406–16. https://doi.org/10.1016/j.tips.2015.04.010.PubMedView ArticleGoogle Scholar
  46. Muller-Wieland D, Knebel B, Haas J, Kotzka J. SREBP-1 and fatty liver. Clinical relevance for diabetes, obesity, dyslipidemia and atherosclerosis. Herz. 2012;37(3):273–8. https://doi.org/10.1007/s00059-012-3608-y.PubMedView ArticleGoogle Scholar
  47. Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol. 2017;24(9):1161–80. https://doi.org/10.1016/j.chembiol.2017.08.028.PubMedView ArticlePubMed CentralGoogle Scholar
  48. Min HY, Lee HY. Oncogene-driven metabolic alterations in cancer. Biomol Ther (Seoul). 2017. https://doi.org/10.4062/biomolther.2017.211.View ArticleGoogle Scholar
  49. Gopal K, Grossi E, Paoletti P, Usardi M. Lipid composition of human intracranial tumors: a biochemical study. Acta Neurochir (Wien). 1963;11:333–47.View ArticleGoogle Scholar
  50. Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18(2):153–61. https://doi.org/10.1016/j.cmet.2013.05.017.PubMedPubMed CentralView ArticleGoogle Scholar
  51. Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology—divergent pathophysiology. Nat Rev Endocrinol. 2017. https://doi.org/10.1038/nrendo.2017.91.PubMedView ArticleGoogle Scholar
  52. Schlosser HA, Drebber U, Urbanski A, Haase S, Baltin C, Berlth F, et al. Glucose transporters 1, 3, 6, and 10 are expressed in gastric cancer and glucose transporter 3 is associated with UICC stage and survival. Gastric Cancer. 2017;20(1):83–91. https://doi.org/10.1007/s10120-015-0577-x.PubMedView ArticleGoogle Scholar
  53. Sharen G, Peng Y, Cheng H, Liu Y, Shi Y, Zhao J. Prognostic value of GLUT-1 expression in pancreatic cancer: results from 538 patients. Oncotarget. 2017;8(12):19760–7. https://doi.org/10.18632/oncotarget.15035.PubMedPubMed CentralView ArticleGoogle Scholar
  54. Sun HW, Yu XJ, Wu WC, Chen J, Shi M, Zheng L, et al. GLUT1 and ASCT2 as predictors for prognosis of hepatocellular carcinoma. PLoS ONE. 2016;11(12):e0168907. https://doi.org/10.1371/journal.pone.0168907.PubMedPubMed CentralView ArticleGoogle Scholar
  55. Cheng C, Ru P, Geng F, Liu J, Yoo JY, Wu X, et al. Glucose-mediated N-glycosylation of SCAP is essential for SREBP-1 activation and tumor growth. Cancer Cell. 2015;28(5):569–81. https://doi.org/10.1016/j.ccell.2015.09.021.PubMedPubMed CentralView ArticleGoogle Scholar
  56. Ryczko MC, Pawling J, Chen R, Abdel Rahman AM, Yau K, Copeland JK, et al. Metabolic reprogramming by hexosamine biosynthetic and golgi N-glycan branching pathways. Sci Rep. 2016;6:23043. https://doi.org/10.1038/srep23043.PubMedPubMed CentralView ArticleGoogle Scholar
  57. Adeva-Andany MM, Perez-Felpete N, Fernandez-Fernandez C, Donapetry-Garcia C, Pazos-Garcia C. Liver glucose metabolism in humans. Biosci Rep. 2016. https://doi.org/10.1042/bsr20160385.PubMedPubMed CentralView ArticleGoogle Scholar
  58. Guo D. SCAP links glucose to lipid metabolism in cancer cells. Mol Cell Oncol. 2016. https://doi.org/10.1080/23723556.2015.1132120.PubMedPubMed CentralView ArticleGoogle Scholar
  59. Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009;15(21):6479–83. https://doi.org/10.1158/1078-0432.CCR-09-0889.PubMedPubMed CentralView ArticleGoogle Scholar
  60. Barger JF, Plas DR. Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis. Endocr Relat Cancer. 2010;17(4):R287–304. https://doi.org/10.1677/ERC-10-0106.PubMedView ArticleGoogle Scholar
  61. Dang CV. Therapeutic targeting of Myc-reprogrammed cancer cell metabolism. Cold Spring Harb Symp Quant Biol. 2011;76:369–74. https://doi.org/10.1101/sqb.2011.76.011296.PubMedView ArticleGoogle Scholar
  62. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA. 2007;104(49):19345–50. https://doi.org/10.1073/pnas.0709747104.PubMedPubMed CentralView ArticleGoogle Scholar
  63. Bergstrom J, Furst P, Noree LO, Vinnars E. Intracellular free amino acid concentration in human muscle tissue. J Appl Physiol. 1974;36(6):693–7.PubMedView ArticleGoogle Scholar
  64. Wishart DS, Jewison T, Guo AC, Wilson M, Knox C, Liu Y, et al. HMDB 3.0–the human metabolome database in 2013. Nucleic Acids Res. 2013;41(Database issue):D801–7. https://doi.org/10.1093/nar/gks1065.PubMedView ArticleGoogle Scholar
  65. DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29(3):313–24. https://doi.org/10.1038/onc.2009.358.PubMedView ArticleGoogle Scholar
  66. Bhutia YD, Babu E, Ramachandran S, Ganapathy V. Amino Acid transporters in cancer and their relevance to “glutamine addiction”: novel targets for the design of a new class of anticancer drugs. Cancer Res. 2015;75(9):1782–8. https://doi.org/10.1158/0008-5472.CAN-14-3745.PubMedView ArticleGoogle Scholar
  67. Erickson JW, Cerione RA. Glutaminase: a hot spot for regulation of cancer cell metabolism? Oncotarget. 2010;1(8):734–40. https://doi.org/10.18632/oncotarget.208.PubMedPubMed CentralView ArticleGoogle Scholar
  68. Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci USA. 2011;108(49):19611–6. https://doi.org/10.1073/pnas.1117773108.PubMedPubMed CentralView ArticleGoogle Scholar
  69. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2012;481(7381):380–4. https://doi.org/10.1038/nature10602.View ArticleGoogle Scholar
  70. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2012;481(7381):385–8. https://doi.org/10.1038/nature10642.View ArticleGoogle Scholar
  71. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012;15(1):110–21. https://doi.org/10.1016/j.cmet.2011.12.009.PubMedPubMed CentralView ArticleGoogle Scholar
  72. Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, et al. Acetate dependence of tumors. Cell. 2014;159(7):1591–602. https://doi.org/10.1016/j.cell.2014.11.020.PubMedPubMed CentralView ArticleGoogle Scholar
  73. Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell. 2014;159(7):1603–14. https://doi.org/10.1016/j.cell.2014.11.025.PubMedPubMed CentralView ArticleGoogle Scholar
  74. Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. 2015;27(1):57–71. https://doi.org/10.1016/j.ccell.2014.12.002.PubMedPubMed CentralView ArticleGoogle Scholar
  75. Peck B, Schulze A. Lipid desaturation - the next step in targeting lipogenesis in cancer? FEBS J. 2016;283(15):2767–78. https://doi.org/10.1111/febs.13681.PubMedView ArticleGoogle Scholar
  76. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29(4):431–8. https://doi.org/10.1161/ATVBAHA.108.179564.PubMedPubMed CentralView ArticleGoogle Scholar
  77. Di Vizio D, Adam RM, Kim J, Kim R, Sotgia F, Williams T, et al. Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase. Cell Cycle. 2008;7(14):2257–67. https://doi.org/10.4161/cc.7.14.6475.PubMedView ArticleGoogle Scholar
  78. Cai Y, Wang J, Zhang L, Wu D, Yu D, Tian X, et al. Expressions of fatty acid synthase and HER2 are correlated with poor prognosis of ovarian cancer. Med Oncol. 2015;32(1):391. https://doi.org/10.1007/s12032-014-0391-z.PubMedView ArticleGoogle Scholar
  79. Long QQ, Yi YX, Qiu J, Xu CJ, Huang PL. Fatty acid synthase (FASN) levels in serum of colorectal cancer patients: correlation with clinical outcomes. Tumour Biol. 2014;35(4):3855–9. https://doi.org/10.1007/s13277-013-1510-8.PubMedView ArticleGoogle Scholar
  80. Witkiewicz AK, Nguyen KH, Dasgupta A, Kennedy EP, Yeo CJ, Lisanti MP, et al. Co-expression of fatty acid synthase and caveolin-1 in pancreatic ductal adenocarcinoma: implications for tumor progression and clinical outcome. Cell Cycle. 2008;7(19):3021–5. https://doi.org/10.4161/cc.7.19.6719.PubMedView ArticleGoogle Scholar
  81. Walter K, Hong SM, Nyhan S, Canto M, Fedarko N, Klein A, et al. Serum fatty acid synthase as a marker of pancreatic neoplasia. Cancer Epidemiol Biomarkers Prev. 2009;18(9):2380–5. https://doi.org/10.1158/1055-9965.EPI-09-0144.PubMedPubMed CentralView ArticleGoogle Scholar
  82. Nohturfft A, Zhang SC. Coordination of lipid metabolism in membrane biogenesis. Annu Rev Cell Dev Biol. 2009;25:539–66. https://doi.org/10.1146/annurev.cellbio.24.110707.175344.PubMedView ArticleGoogle Scholar
  83. Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest. 1997;99(5):846–54. https://doi.org/10.1172/JCI119248.PubMedPubMed CentralView ArticleGoogle Scholar
  84. Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS. Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J Clin Invest. 1997;99(5):838–45. https://doi.org/10.1172/JCI119247.PubMedPubMed CentralView ArticleGoogle Scholar
  85. Wang X, Sato R, Brown MS, Hua X, Goldstein JL. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell. 1994;77(1):53–62.PubMedView ArticleGoogle Scholar
  86. Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, et al. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell. 1993;75(1):187–97.PubMedView ArticleGoogle Scholar
  87. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109(9):1125–31. https://doi.org/10.1172/JCI15593.PubMedPubMed CentralView ArticleGoogle Scholar
  88. Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA. 2003;100(21):12027–32. https://doi.org/10.1073/pnas.1534923100.PubMedPubMed CentralView ArticleGoogle Scholar
  89. Horton JD, Shimomura I, Ikemoto S, Bashmakov Y, Hammer RE. Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver. J Biol Chem. 2003;278(38):36652–60. https://doi.org/10.1074/jbc.M306540200.PubMedView ArticleGoogle Scholar
  90. Hua X, Wu J, Goldstein JL, Brown MS, Hobbs HH. Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes 17p11.2 and 22q13. Genomics. 1995;25(3):667–73.PubMedView ArticleGoogle Scholar
  91. Hua X, Yokoyama C, Wu J, Briggs MR, Brown MS, Goldstein JL, et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc Natl Acad Sci USA. 1993;90(24):11603–7.PubMedPubMed CentralView ArticleGoogle Scholar
  92. Shimano H, Shimomura I, Hammer RE, Herz J, Goldstein JL, Brown MS, et al. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J Clin Invest. 1997;100(8):2115–24. https://doi.org/10.1172/JCI119746.PubMedPubMed CentralView ArticleGoogle Scholar
  93. Lee PC, Sever N, Debose-Boyd RA. Isolation of sterol-resistant Chinese hamster ovary cells with genetic deficiencies in both Insig-1 and Insig-2. J Biol Chem. 2005;280(26):25242–9. https://doi.org/10.1074/jbc.M502989200.PubMedView ArticleGoogle Scholar
  94. Sun LP, Li L, Goldstein JL, Brown MS. Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro. J Biol Chem. 2005;280(28):26483–90. https://doi.org/10.1074/jbc.M504041200.PubMedView ArticleGoogle Scholar
  95. Sun LP, Seemann J, Goldstein JL, Brown MS. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins. Proc Natl Acad Sci USA. 2007;104(16):6519–26. https://doi.org/10.1073/pnas.0700907104.PubMedPubMed CentralView ArticleGoogle Scholar
  96. Nohturfft A, Yabe D, Goldstein JL, Brown MS, Espenshade PJ. Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell. 2000;102(3):315–23.PubMedView ArticleGoogle Scholar
  97. Espenshade PJ, Li WP, Yabe D. Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER. Proc Natl Acad Sci USA. 2002;99(18):11694–9. https://doi.org/10.1073/pnas.182412799.PubMedPubMed CentralView ArticleGoogle Scholar
  98. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell. 2002;110(4):489–500.PubMedView ArticleGoogle Scholar
  99. Adams CM, Goldstein JL, Brown MS. Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles. Proc Natl Acad Sci USA. 2003;100(19):10647–52. https://doi.org/10.1073/pnas.1534833100.PubMedPubMed CentralView ArticleGoogle Scholar
  100. Adams CM, Reitz J, De Brabander JK, Feramisco JD, Li L, Brown MS, et al. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs. J Biol Chem. 2004;279(50):52772–80. https://doi.org/10.1074/jbc.M410302200.PubMedView ArticleGoogle Scholar
  101. Ru P, Hu P, Geng F, Mo X, Cheng C, Yoo JY, et al. Feedback loop regulation of SCAP/SREBP-1 by miR-29 modulates EGFR signaling-driven glioblastoma growth. Cell Rep. 2016;16(6):1527–35. https://doi.org/10.1016/j.celrep.2016.07.017.PubMedPubMed CentralView ArticleGoogle Scholar
  102. Ru P, Guo D. microRNA-29 mediates a novel negative feedback loop to regulate SCAP/SREBP-1 and lipid metabolism. RNA Dis. 2017. https://doi.org/10.14800/rd.1525.PubMedPubMed CentralView ArticleGoogle Scholar
  103. Guo D. SCAP links glucose to lipid metabolism in cancer cells. Mol Cell Oncol. 2016. https://doi.org/10.1080/23723556.2015.1132120.PubMedPubMed CentralView ArticleGoogle Scholar
  104. Shao W, Espenshade PJ. Sugar makes fat by talking to SCAP. Cancer Cell. 2015;28(5):548–9. https://doi.org/10.1016/j.ccell.2015.10.011.PubMedPubMed CentralView ArticleGoogle Scholar
  105. Cheng C, Guo JY, Geng F, Wu X, Cheng X, Li Q, et al. Analysis of SCAP N-glycosylation and trafficking in human cells. J Vis Exp. 2016. https://doi.org/10.3791/54709.View ArticlePubMedPubMed CentralGoogle Scholar
  106. Guo D, Hildebrandt IJ, Prins RM, Soto H, Mazzotta MM, Dang J, et al. The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proc Natl Acad Sci USA. 2009;106(31):12932–7. https://doi.org/10.1073/pnas.0906606106.PubMedPubMed CentralView ArticleGoogle Scholar
  107. Ru P, Williams TM, Chakravarti A, Guo D. Tumor metabolism of malignant gliomas. Cancers (Basel). 2013;5(4):1469–84. https://doi.org/10.3390/cancers5041469.View ArticleGoogle Scholar
  108. Guo D, Bell EH, Mischel P, Chakravarti A. Targeting SREBP-1-driven lipid metabolism to treat cancer. Curr Pharm Des. 2014;20(15):2619–26.PubMedPubMed CentralView ArticleGoogle Scholar
  109. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492–507. https://doi.org/10.1056/NEJMra0708126.PubMedView ArticleGoogle Scholar
  110. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66. https://doi.org/10.1016/S1470-2045(09)70025-7.PubMedView ArticleGoogle Scholar
  111. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007;21(21):2683–710.PubMedView ArticleGoogle Scholar
  112. Paleologos NA, Merrell RT. Anaplastic glioma. Curr Treat Options Neurol. 2012;14(4):381–90. https://doi.org/10.1007/s11940-012-0177-6.PubMedView ArticleGoogle Scholar
  113. Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre JY. Primary brain tumours in adults. Lancet. 2012;379(9830):1984–96. https://doi.org/10.1016/S0140-6736(11)61346-9.PubMedView ArticleGoogle Scholar
  114. Huang HS, Nagane M, Klingbeil CK, Lin H, Nishikawa R, Ji XD, et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem. 1997;272(5):2927–35.PubMedView ArticleGoogle Scholar
  115. Yoshimoto K, Dang J, Zhu S, Nathanson D, Huang T, Dumont R, et al. Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples. Clin Cancer Res. 2008;14(2):488–93. https://doi.org/10.1158/1078-0432.CCR-07-1966.PubMedView ArticleGoogle Scholar
  116. Du X, Kristiana I, Wong J, Brown AJ. Involvement of Akt in ER-to-Golgi transport of SCAP/SREBP: a link between a key cell proliferative pathway and membrane synthesis. Mol Biol Cell. 2006;17(6):2735–45. https://doi.org/10.1091/mbc.E05-11-1094.PubMedPubMed CentralView ArticleGoogle Scholar
  117. Porstmann T, Griffiths B, Chung YL, Delpuech O, Griffiths JR, Downward J, et al. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene. 2005;24(43):6465–81. https://doi.org/10.1038/sj.onc.1208802.PubMedView ArticleGoogle Scholar
  118. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008;8(3):224–36. https://doi.org/10.1016/j.cmet.2008.07.007.PubMedPubMed CentralView ArticleGoogle Scholar
  119. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010;39(2):171–83. https://doi.org/10.1016/j.molcel.2010.06.022.PubMedPubMed CentralView ArticleGoogle Scholar
  120. Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI, et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 2011;14(1):21–32. https://doi.org/10.1016/j.cmet.2011.06.002.PubMedPubMed CentralView ArticleGoogle Scholar
  121. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell. 2011;146(3):408–20. https://doi.org/10.1016/j.cell.2011.06.034.PubMedPubMed CentralView ArticleGoogle Scholar
  122. Ricoult SJ, Yecies JL, Ben-Sahra I, Manning BD. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene. 2015. https://doi.org/10.1038/onc.2015.179.PubMedPubMed CentralView ArticleGoogle Scholar
  123. Williams KJ, Argus JP, Zhu Y, Wilks MQ, Marbois BN, York AG, et al. An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. Cancer Res. 2013;73(9):2850–62. https://doi.org/10.1158/0008-5472.CAN-13-0382-T.PubMedPubMed CentralView ArticleGoogle Scholar
  124. von Roemeling CA, Marlow LA, Wei JJ, Cooper SJ, Caulfield TR, Wu K, et al. Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Clin Cancer Res. 2013;19(9):2368–80. https://doi.org/10.1158/1078-0432.CCR-12-3249.View ArticleGoogle Scholar
  125. Li N, Zhou ZS, Shen Y, Xu J, Miao HH, Xiong Y, et al. Inhibition of the sterol regulatory element-binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice. Hepatology. 2017;65(6):1936–47. https://doi.org/10.1002/hep.29018.PubMedView ArticleGoogle Scholar
  126. Kamisuki S, Mao Q, Abu-Elheiga L, Gu Z, Kugimiya A, Kwon Y, et al. A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem Biol. 2009;16(8):882–92. https://doi.org/10.1016/j.chembiol.2009.07.007.PubMedView ArticleGoogle Scholar
  127. Li X, Chen YT, Hu P, Huang WC. Fatostatin displays high antitumor activity in prostate cancer by blocking SREBP-regulated metabolic pathways and androgen receptor signaling. Mol Cancer Ther. 2014;13(4):855–66. https://doi.org/10.1158/1535-7163.MCT-13-0797.PubMedPubMed CentralView ArticleGoogle Scholar
  128. Li X, Wu JB, Chung LW, Huang WC. Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations. Oncotarget. 2015;6(38):41018–32. https://doi.org/10.18632/oncotarget.5879.PubMedPubMed CentralView ArticleGoogle Scholar
  129. Krol SK, Kielbus M, Rivero-Muller A, Stepulak A. Comprehensive review on betulin as a potent anticancer agent. Biomed Res Int. 2015;2015:584189. https://doi.org/10.1155/2015/584189.PubMedPubMed CentralView ArticleGoogle Scholar
  130. Gholkar AA, Cheung K, Williams KJ, Lo YC, Hamideh SA, Nnebe C, et al. Fatostatin inhibits cancer cell proliferation by affecting mitotic microtubule spindle assembly and cell division. J Biol Chem. 2016;291(33):17001–8. https://doi.org/10.1074/jbc.C116.737346.PubMedPubMed CentralView ArticleGoogle Scholar
  131. Shao W, Machamer CE, Espenshade PJ. Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner. J Lipid Res. 2016;57(8):1564–73. https://doi.org/10.1194/jlr.M069583.PubMedPubMed CentralView ArticleGoogle Scholar
  132. Miyata S, Inoue J, Shimizu M, Sato R. Xanthohumol improves diet-induced obesity and fatty liver by suppressing sterol regulatory element-binding protein (SREBP) activation. J Biol Chem. 2015;290(33):20565–79. https://doi.org/10.1074/jbc.M115.656975.PubMedPubMed CentralView ArticleGoogle Scholar
  133. Soica C, Dehelean C, Danciu C, Wang HM, Wenz G, Ambrus R, et al. Betulin complex in gamma-cyclodextrin derivatives: properties and antineoplasic activities in in vitro and in vivo tumor models. Int J Mol Sci. 2012;13(11):14992–5011. https://doi.org/10.3390/ijms131114992.PubMedPubMed CentralView ArticleGoogle Scholar
  134. Shikata Y, Yoshimaru T, Komatsu M, Katoh H, Sato R, Kanagaki S, et al. Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor. Cancer Sci. 2017;108(4):785–94. https://doi.org/10.1111/cas.13175.PubMedPubMed CentralView ArticleGoogle Scholar
  135. Dokduang H, Yongvanit P, Namwat N, Pairojkul C, Sangkhamanon S, Yageta MS, et al. Xanthohumol inhibits STAT3 activation pathway leading to growth suppression and apoptosis induction in human cholangiocarcinoma cells. Oncol Rep. 2016;35(4):2065–72. https://doi.org/10.3892/or.2016.4584.PubMedView ArticleGoogle Scholar
  136. Jiang W, Zhao S, Xu L, Lu Y, Lu Z, Chen C, et al. The inhibitory effects of xanthohumol, a prenylated chalcone derived from hops, on cell growth and tumorigenesis in human pancreatic cancer. Biomed Pharmacother. 2015;73:40–7. https://doi.org/10.1016/j.biopha.2015.05.020.PubMedView ArticleGoogle Scholar
  137. Monteiro R, Calhau C, Silva AO, Pinheiro-Silva S, Guerreiro S, Gartner F, et al. Xanthohumol inhibits inflammatory factor production and angiogenesis in breast cancer xenografts. J Cell Biochem. 2008;104(5):1699–707. https://doi.org/10.1002/jcb.21738.PubMedView ArticleGoogle Scholar
  138. Li X, Wu JB, Li Q, Shigemura K, Chung LW, Huang WC. SREBP-2 promotes stem cell-like properties and metastasis by transcriptional activation of c-Myc in prostate cancer. Oncotarget. 2016;7(11):12869–84. https://doi.org/10.18632/oncotarget.7331.PubMedPubMed CentralView ArticleGoogle Scholar
  139. Vallianou NG, Kostantinou A, Kougias M, Kazazis C. Statins and cancer. Anticancer Agents Med Chem. 2014;14(5):706–12.PubMedView ArticleGoogle Scholar
  140. Osmak M. Statins and cancer: current and future prospects. Cancer Lett. 2012;324(1):1–12. https://doi.org/10.1016/j.canlet.2012.04.011.PubMedView ArticleGoogle Scholar
  141. Zhang J, Yang Z, Xie L, Xu L, Xu D, Liu X. Statins, autophagy and cancer metastasis. Int J Biochem Cell Biol. 2013;45(3):745–52. https://doi.org/10.1016/j.biocel.2012.11.001.PubMedView ArticleGoogle Scholar
  142. Bathaie SZ, Ashrafi M, Azizian M, Tamanoi F. Mevalonate pathway and human cancers. Curr Mol Pharmacol. 2017;10(2):77–85. https://doi.org/10.2174/1874467209666160112123205.PubMedView ArticleGoogle Scholar
  143. Nayan M, Punjani N, Juurlink DN, Finelli A, Austin PC, Kulkarni GS, et al. Statin use and kidney cancer survival outcomes: a systematic review and meta-analysis. Cancer Treat Rev. 2017;52:105–16. https://doi.org/10.1016/j.ctrv.2016.11.009.PubMedView ArticleGoogle Scholar
  144. Pandyra AA, Mullen PJ, Goard CA, Ericson E, Sharma P, Kalkat M, et al. Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death. Oncotarget. 2015;6(29):26909–21. https://doi.org/10.18632/oncotarget.4817.PubMedPubMed CentralView ArticleGoogle Scholar
  145. Nayan M, Finelli A, Jewett MA, Juurlink DN, Austin PC, Kulkarni GS, et al. Statin use and kidney cancer outcomes a propensity score analysis. Urol Oncol. 2016;34(11):487-e1–6. https://doi.org/10.1016/j.urolonc.2016.06.007.View ArticleGoogle Scholar
  146. Pandyra A, Penn LZ. Targeting tumor cell metabolism via the mevalonate pathway: two hits are better than one. Mol Cell Oncol. 2014;1(4):e969133. https://doi.org/10.4161/23723548.2014.969133.PubMedPubMed CentralView ArticleGoogle Scholar
  147. Pandyra A, Mullen PJ, Kalkat M, Yu R, Pong JT, Li Z, et al. Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop. Cancer Res. 2014;74(17):4772–82. https://doi.org/10.1158/0008-5472.CAN-14-0130.PubMedView ArticleGoogle Scholar
  148. Catalina-Rodriguez O, Kolukula VK, Tomita Y, Preet A, Palmieri F, Wellstein A, et al. The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget. 2012;3(10):1220–35. https://doi.org/10.18632/oncotarget.714.PubMedPubMed CentralView ArticleGoogle Scholar
  149. Convertini P, Menga A, Andria G, Scala I, Santarsiero A, Castiglione Morelli MA, et al. The contribution of the citrate pathway to oxidative stress in Down syndrome. Immunology. 2016;149(4):423–31. https://doi.org/10.1111/imm.12659.PubMedPubMed CentralView ArticleGoogle Scholar
  150. Infantino V, Iacobazzi V, De Santis F, Mastrapasqua M, Palmieri F. Transcription of the mitochondrial citrate carrier gene: role of SREBP-1, upregulation by insulin and downregulation by PUFA. Biochem Biophys Res Commun. 2007;356(1):249–54. https://doi.org/10.1016/j.bbrc.2007.02.114.PubMedView ArticleGoogle Scholar
  151. Kolukula VK, Sahu G, Wellstein A, Rodriguez OC, Preet A, Iacobazzi V, et al. SLC25A1, or CIC, is a novel transcriptional target of mutant p53 and a negative tumor prognostic marker. Oncotarget. 2014;5(5):1212–25. https://doi.org/10.18632/oncotarget.1831.PubMedPubMed CentralView ArticleGoogle Scholar
  152. Assmann N, O’Brien KL, Donnelly RP, Dyck L, Zaiatz-Bittencourt V, Loftus RM, et al. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat Immunol. 2017;18(11):1197–206. https://doi.org/10.1038/ni.3838.PubMedView ArticleGoogle Scholar
  153. Zhao S, Torres A, Henry RA, Trefely S, Wallace M, Lee JV, et al. ATP-citrate lyase controls a glucose-to-acetate metabolic switch. Cell Rep. 2016;17(4):1037–52. https://doi.org/10.1016/j.celrep.2016.09.069.PubMedPubMed CentralView ArticleGoogle Scholar
  154. He Y, Gao M, Cao Y, Tang H, Liu S, Tao Y. Nuclear localization of metabolic enzymes in immunity and metastasis. Biochim Biophys Acta. 2017;1868(2):359–71. https://doi.org/10.1016/j.bbcan.2017.07.002.PubMedView ArticleGoogle Scholar
  155. Zaidi N, Swinnen JV, Smans K. ATP-citrate lyase: a key player in cancer metabolism. Cancer Res. 2012;72(15):3709–14. https://doi.org/10.1158/0008-5472.CAN-11-4112.PubMedView ArticleGoogle Scholar
  156. Moon YA, Lee JJ, Park SW, Ahn YH, Kim KS. The roles of sterol regulatory element-binding proteins in the transactivation of the rat ATP citrate-lyase promoter. J Biol Chem. 2000;275(39):30280–6. https://doi.org/10.1074/jbc.M001066200.PubMedView ArticleGoogle Scholar
  157. Sato R, Okamoto A, Inoue J, Miyamoto W, Sakai Y, Emoto N, et al. Transcriptional regulation of the ATP citrate-lyase gene by sterol regulatory element-binding proteins. J Biol Chem. 2000;275(17):12497–502.PubMedView ArticleGoogle Scholar
  158. Amemiya-Kudo M, Shimano H, Hasty AH, Yahagi N, Yoshikawa T, Matsuzaka T, et al. Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes. J Lipid Res. 2002;43(8):1220–35.PubMedGoogle Scholar
  159. Khwairakpam AD, Shyamananda MS, Sailo BL, Rathnakaram SR, Padmavathi G, Kotoky J, et al. ATP citrate lyase (ACLY): a promising target for cancer prevention and treatment. Curr Drug Targets. 2015;16(2):156–63.PubMedView ArticleGoogle Scholar
  160. Osugi J, Yamaura T, Muto S, Okabe N, Matsumura Y, Hoshino M, et al. Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer. Lung Cancer. 2015;88(3):310–8. https://doi.org/10.1016/j.lungcan.2015.03.004.PubMedView ArticleGoogle Scholar
  161. Csanadi A, Kayser C, Donauer M, Gumpp V, Aumann K, Rawluk J, et al. Prognostic value of malic enzyme and ATP-citrate lyase in non-small cell lung cancer of the young and the elderly. PLoS ONE. 2015;10(5):e0126357. https://doi.org/10.1371/journal.pone.0126357.PubMedPubMed CentralView ArticleGoogle Scholar
  162. Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005;8(4):311–21. https://doi.org/10.1016/j.ccr.2005.09.008.PubMedView ArticleGoogle Scholar
  163. Lee JH, Jang H, Lee SM, Lee JE, Choi J, Kim TW, et al. ATP-citrate lyase regulates cellular senescence via an AMPK- and p53-dependent pathway. FEBS J. 2015;282(2):361–71. https://doi.org/10.1111/febs.13139.PubMedView ArticleGoogle Scholar
  164. Hanai JI, Doro N, Seth P, Sukhatme VP. ATP citrate lyase knockdown impacts cancer stem cells in vitro. Cell Death Dis. 2013;4:e696. https://doi.org/10.1038/cddis.2013.215.PubMedPubMed CentralView ArticleGoogle Scholar
  165. Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB. ATP citrate lyase is an important component of cell growth and transformation. Oncogene. 2005;24(41):6314–22. https://doi.org/10.1038/sj.onc.1208773.PubMedView ArticleGoogle Scholar
  166. Watkins PA, Maiguel D, Jia Z, Pevsner J. Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J Lipid Res. 2007;48(12):2736–50. https://doi.org/10.1194/jlr.M700378-JLR200.PubMedView ArticleGoogle Scholar
  167. Xu H, Luo J, Ma G, Zhang X, Yao D, Li M, et al. Acyl-CoA synthetase short-chain family member 2 (ACSS2) is regulated by SREBP-1 and plays a role in fatty acid synthesis in caprine mammary epithelial cells. J Cell Physiol. 2018;233(2):1005–16. https://doi.org/10.1002/jcp.25954.PubMedView ArticleGoogle Scholar
  168. Sun L, Kong Y, Cao M, Zhou H, Li H, Cui Y, et al. Decreased expression of acetyl-CoA synthase 2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma. Cancer Sci. 2017;108(7):1338–46. https://doi.org/10.1111/cas.13252.PubMedPubMed CentralView ArticleGoogle Scholar
  169. Gao X, Lin SH, Ren F, Li JT, Chen JJ, Yao CB, et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat Commun. 2016;7:11960. https://doi.org/10.1038/ncomms11960.PubMedPubMed CentralView ArticleGoogle Scholar
  170. Yu T, Cui L, Liu C, Wang G, Wu T, Huang Y. Expression of acetyl coenzyme A synthetase 2 in colorectal cancer and its biological role. Zhonghua Wei Chang Wai Ke Za Zhi. 2017;20(10):1174–9.PubMedGoogle Scholar
  171. Lakhter AJ, Hamilton J, Konger RL, Brustovetsky N, Broxmeyer HE, Naidu SR. Glucose-independent acetate metabolism promotes melanoma cell survival and tumor growth. J Biol Chem. 2016;291(42):21869–79. https://doi.org/10.1074/jbc.M115.712166.PubMedPubMed CentralView ArticleGoogle Scholar
  172. Yun M, Bang SH, Kim JW, Park JY, Kim KS, Lee JD. The importance of acetyl coenzyme A synthetase for 11C-acetate uptake and cell survival in hepatocellular carcinoma. J Nucl Med. 2009;50(8):1222–8. https://doi.org/10.2967/jnumed.109.062703.PubMedView ArticleGoogle Scholar
  173. Yoshii Y, Waki A, Furukawa T, Kiyono Y, Mori T, Yoshii H, et al. Tumor uptake of radiolabeled acetate reflects the expression of cytosolic acetyl-CoA synthetase: implications for the mechanism of acetate PET. Nucl Med Biol. 2009;36(7):771–7. https://doi.org/10.1016/j.nucmedbio.2009.05.006.PubMedView ArticleGoogle Scholar
  174. Li X, Yu W, Qian X, Xia Y, Zheng Y, Lee JH, et al. Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol Cell. 2017;66(5):684–97. https://doi.org/10.1016/j.molcel.2017.04.026.PubMedView ArticlePubMed CentralGoogle Scholar
  175. Li X, Qian X, Lu Z. Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Autophagy. 2017;13(10):1790–1. https://doi.org/10.1080/15548627.2017.1349581.PubMedView ArticlePubMed CentralGoogle Scholar
  176. Wang C, Rajput S, Watabe K, Liao DF, Cao D. Acetyl-CoA carboxylase-a as a novel target for cancer therapy. Front Biosci (Schol Ed). 2010;2:515–26.Google Scholar
  177. Zu X, Zhong J, Luo D, Tan J, Zhang Q, Wu Y, et al. Chemical genetics of acetyl-CoA carboxylases. Molecules. 2013;18(2):1704–19. https://doi.org/10.3390/molecules18021704.PubMedView ArticleGoogle Scholar
  178. Su YW, Lin YH, Pai MH, Lo AC, Lee YC, Fang IC, et al. Association between phosphorylated AMP-activated protein kinase and acetyl-CoA carboxylase expression and outcome in patients with squamous cell carcinoma of the head and neck. PLoS ONE. 2014;9(4):e96183. https://doi.org/10.1371/journal.pone.0096183.PubMedPubMed CentralView ArticleGoogle Scholar
  179. Pizer ES, Thupari J, Han WF, Pinn ML, Chrest FJ, Frehywot GL, et al. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res. 2000;60(2):213–8.PubMedGoogle Scholar
  180. Guseva NV, Rokhlin OW, Glover RA, Cohen MB. TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status. Cancer Biol Ther. 2011;12(1):80–5. https://doi.org/10.4161/cbt.12.1.15721.PubMedView ArticleGoogle Scholar
  181. Li S, Qiu L, Wu B, Shen H, Zhu J, Zhou L, et al. TOFA suppresses ovarian cancer cell growth in vitro and in vivo. Mol Med Rep. 2013;8(2):373–8. https://doi.org/10.3892/mmr.2013.1505.PubMedView ArticleGoogle Scholar
  182. Tan W, Zhong Z, Wang S, Suo Z, Yang X, Hu X, et al. Berberine regulated lipid metabolism in the presence of C75, compound C, and TOFA in breast cancer cell line MCF-7. Evid Based Complement Altern Med. 2015;2015:396035. https://doi.org/10.1155/2015/396035.View ArticleGoogle Scholar
  183. Wang C, Xu C, Sun M, Luo D, Liao DF, Cao D. Acetyl-CoA carboxylase-alpha inhibitor TOFA induces human cancer cell apoptosis. Biochem Biophys Res Commun. 2009;385(3):302–6. https://doi.org/10.1016/j.bbrc.2009.05.045.PubMedPubMed CentralView ArticleGoogle Scholar
  184. Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, Brun SN, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med. 2016;22(10):1108–19. https://doi.org/10.1038/nm.4181.PubMedPubMed CentralView ArticleGoogle Scholar
  185. Luo J, Hong Y, Lu Y, Qiu S, Chaganty BK, Zhang L, et al. Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab. Cancer Lett. 2017;384:39–49. https://doi.org/10.1016/j.canlet.2016.09.020.PubMedView ArticleGoogle Scholar
  186. Jones JE, Esler WP, Patel R, Lanba A, Vera NB, Pfefferkorn JA, et al. Inhibition of acetyl-CoA carboxylase 1 (ACC1) and 2 (ACC2) reduces proliferation and de novo lipogenesis of EGFRvIII human glioblastoma cells. PLoS ONE. 2017;12(1):e0169566. https://doi.org/10.1371/journal.pone.0169566.PubMedPubMed CentralView ArticleGoogle Scholar
  187. Menendez JA, Lupu R. Fatty acid synthase (FASN) as a therapeutic target in breast cancer. Expert Opin Ther Targets. 2017. https://doi.org/10.1080/14728222.2017.1381087.PubMedView ArticleGoogle Scholar
  188. Menendez JA, Vellon L, Mehmi I, Oza BP, Ropero S, Colomer R, et al. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci USA. 2004;101(29):10715–20. https://doi.org/10.1073/pnas.0403390101.PubMedPubMed CentralView ArticleGoogle Scholar
  189. Visca P, Sebastiani V, Botti C, Diodoro MG, Lasagni RP, Romagnoli F, et al. Fatty acid synthase (FAS) is a marker of increased risk of recurrence in lung carcinoma. Anticancer Res. 2004;24(6):4169–73.PubMedGoogle Scholar
  190. Merino Salvador M, Gomez de Cedron M, Merino Rubio J, Falagan Martinez S, Sanchez Martinez R, Casado E, et al. Lipid metabolism and lung cancer. Crit Rev Oncol Hematol. 2017;112:31–40. https://doi.org/10.1016/j.critrevonc.2017.02.001.PubMedView ArticleGoogle Scholar
  191. Jones SF, Infante JR. Molecular pathways: fatty acid synthase. Clin Cancer Res. 2015;21(24):5434–8. https://doi.org/10.1158/1078-0432.CCR-15-0126.PubMedView ArticleGoogle Scholar
  192. Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 2004;64(6):2070–5.PubMedView ArticleGoogle Scholar
  193. Carvalho MA, Zecchin KG, Seguin F, Bastos DC, Agostini M, Rangel AL, et al. Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model. Int J Cancer. 2008;123(11):2557–65. https://doi.org/10.1002/ijc.23835.PubMedView ArticleGoogle Scholar
  194. Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA. 1994;91(14):6379–83.PubMedPubMed CentralView ArticleGoogle Scholar
  195. Pizer ES, Wood FD, Heine HS, Romantsev FE, Pasternack GR, Kuhajda FP. Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res. 1996;56(6):1189–93.PubMedGoogle Scholar
  196. Pizer ES, Jackisch C, Wood FD, Pasternack GR, Davidson NE, Kuhajda FP. Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res. 1996;56(12):2745–7.PubMedGoogle Scholar
  197. Li JN, Gorospe M, Chrest FJ, Kumaravel TS, Evans MK, Han WF, et al. Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res. 2001;61(4):1493–9.PubMedGoogle Scholar
  198. Zhou W, Simpson PJ, McFadden JM, Townsend CA, Medghalchi SM, Vadlamudi A, et al. Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. Cancer Res. 2003;63(21):7330–7.PubMedGoogle Scholar
  199. Menendez JA, Vellon L, Colomer R, Lupu R. Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity. Int J Cancer. 2005;115(1):19–35. https://doi.org/10.1002/ijc.20754.PubMedView ArticleGoogle Scholar
  200. Gabrielson EW, Pinn ML, Testa JR, Kuhajda FP. Increased fatty acid synthase is a therapeutic target in mesothelioma. Clin Cancer Res. 2001;7(1):153–7.PubMedGoogle Scholar
  201. Horiguchi A, Asano T, Asano T, Ito K, Sumitomo M, Hayakawa M. Pharmacological inhibitor of fatty acid synthase suppresses growth and invasiveness of renal cancer cells. J Urol. 2008;180(2):729–36. https://doi.org/10.1016/j.juro.2008.03.186.PubMedView ArticleGoogle Scholar
  202. Relat J, Blancafort A, Oliveras G, Cufi S, Haro D, Marrero PF, et al. Different fatty acid metabolism effects of (−)-epigallocatechin-3-gallate and C75 in adenocarcinoma lung cancer. BMC Cancer. 2012;12:280. https://doi.org/10.1186/1471-2407-12-280.PubMedPubMed CentralView ArticleGoogle Scholar
  203. Chen HW, Chang YF, Chuang HY, Tai WT, Hwang JJ. Targeted therapy with fatty acid synthase inhibitors in a human prostate carcinoma LNCaP/tk-luc-bearing animal model. Prostate Cancer Prostatic Dis. 2012;15(3):260–4. https://doi.org/10.1038/pcan.2012.15.PubMedView ArticleGoogle Scholar
  204. Flavin R, Peluso S, Nguyen PL, Loda M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010;6(4):551–62. https://doi.org/10.2217/fon.10.11.PubMedPubMed CentralView ArticleGoogle Scholar
  205. Mullen GE, Yet L. Progress in the development of fatty acid synthase inhibitors as anticancer targets. Bioorg Med Chem Lett. 2015;25(20):4363–9. https://doi.org/10.1016/j.bmcl.2015.08.087.PubMedView ArticleGoogle Scholar
  206. Enoch HG, Catala A, Strittmatter P. Mechanism of rat liver microsomal stearyl-CoA desaturase. Studies of the substrate specificity, enzyme-substrate interactions, and the function of lipid. J Biol Chem. 1976;251(16):5095–103.PubMedGoogle Scholar
  207. Bai Y, McCoy JG, Levin EJ, Sobrado P, Rajashankar KR, Fox BG, et al. X-ray structure of a mammalian stearoyl-CoA desaturase. Nature. 2015;524(7564):252–6. https://doi.org/10.1038/nature14549.PubMedPubMed CentralView ArticleGoogle Scholar
  208. Ntambi JM, Miyazaki M. Regulation of stearoyl-CoA desaturases and role in metabolism. Prog Lipid Res. 2004;43(2):91–104.PubMedView ArticleGoogle Scholar
  209. Ntambi JM, Miyazaki M, Dobrzyn A. Regulation of stearoyl-CoA desaturase expression. Lipids. 2004;39(11):1061–5.PubMedView ArticleGoogle Scholar
  210. Wu X, Zou X, Chang Q, Zhang Y, Li Y, Zhang L, et al. The evolutionary pattern and the regulation of stearoyl-CoA desaturase genes. Biomed Res Int. 2013;2013:856521. https://doi.org/10.1155/2013/856521.PubMedPubMed CentralView ArticleGoogle Scholar
  211. Zhang Z, Dales NA, Winther MD. Opportunities and challenges in developing stearoyl-coenzyme A desaturase-1 inhibitors as novel therapeutics for human disease. J Med Chem. 2014;57(12):5039–56. https://doi.org/10.1021/jm401516c.PubMedView ArticleGoogle Scholar
  212. Fritz V, Benfodda Z, Rodier G, Henriquet C, Iborra F, Avances C, et al. Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice. Mol Cancer Ther. 2010;9(6):1740–54. https://doi.org/10.1158/1535-7163.MCT-09-1064.PubMedPubMed CentralView ArticleGoogle Scholar
  213. Peck B, Schug ZT, Zhang Q, Dankworth B, Jones DT, Smethurst E, et al. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments. Cancer Metab. 2016;4:6. https://doi.org/10.1186/s40170-016-0146-8.PubMedPubMed CentralView ArticleGoogle Scholar
  214. Yu DC, Bury JP, Tiernan J, Waby JS, Staton CA, Corfe BM. Short-chain fatty acid level and field cancerization show opposing associations with enteroendocrine cell number and neuropilin expression in patients with colorectal adenoma. Mol Cancer. 2011;10:27. https://doi.org/10.1186/1476-4598-10-27.PubMedPubMed CentralView ArticleGoogle Scholar
  215. Noto A, Raffa S, De Vitis C, Roscilli G, Malpicci D, Coluccia P, et al. Stearoyl-CoA desaturase-1 is a key factor for lung cancer-initiating cells. Cell Death Dis. 2013;4:e947. https://doi.org/10.1038/cddis.2013.444.PubMedPubMed CentralView ArticleGoogle Scholar
  216. Glatz JF, Luiken JJ. From fat to FAT (CD36/SR-B2): understanding the regulation of cellular fatty acid uptake. Biochimie. 2017;136:21–6. https://doi.org/10.1016/j.biochi.2016.12.007.PubMedView ArticleGoogle Scholar
  217. Pohl J, Ring A, Korkmaz U, Ehehalt R, Stremmel W. FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts. Mol Biol Cell. 2005;16(1):24–31. https://doi.org/10.1091/mbc.E04-07-0616.PubMedPubMed CentralView ArticleGoogle Scholar
  218. Maxfield FR, Tabas I. Role of cholesterol and lipid organization in disease. Nature. 2005;438(7068):612–21. https://doi.org/10.1038/nature04399.PubMedView ArticleGoogle Scholar
  219. Rudling MJ, Angelin B, Peterson CO, Collins VP. Low density lipoprotein receptor activity in human intracranial tumors and its relation to the cholesterol requirement. Cancer Res. 1990;50(3):483–7.PubMedGoogle Scholar
  220. Walther TC, Farese RV Jr. The life of lipid droplets. Biochim Biophys Acta. 2009;1791(6):459–66. https://doi.org/10.1016/j.bbalip.2008.10.009.PubMedView ArticleGoogle Scholar
  221. Walther TC, Farese RV Jr. Lipid droplets and cellular lipid metabolism. Annu Rev Biochem. 2012;81:687–714. https://doi.org/10.1146/annurev-biochem-061009-102430.PubMedPubMed CentralView ArticleGoogle Scholar
  222. Fei W, Shui G, Zhang Y, Krahmer N, Ferguson C, Kapterian TS, et al. A role for phosphatidic acid in the formation of “supersized” lipid droplets. PLoS Genet. 2011;7(7):e1002201. https://doi.org/10.1371/journal.pgen.1002201.PubMedPubMed CentralView ArticleGoogle Scholar
  223. Karantonis HC, Nomikos T, Demopoulos CA. Triacylglycerol metabolism. Curr Drug Targets. 2009;10(4):302–19.PubMedView ArticleGoogle Scholar
  224. Harris CA, Haas JT, Streeper RS, Stone SJ, Kumari M, Yang K, et al. DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes. J Lipid Res. 2011;52(4):657–67. https://doi.org/10.1194/jlr.M013003.PubMedPubMed CentralView ArticleGoogle Scholar
  225. Tosi MR, Tugnoli V. Cholesteryl esters in malignancy. Clin Chim Acta. 2005;359(1–2):27–45. https://doi.org/10.1016/j.cccn.2005.04.003.PubMedView ArticleGoogle Scholar
  226. Tugnoli V, Tosi MR. Cholesteryl ester detection in a human urothelial carcinoma. Clin Chim Acta. 2005;360(1–2):208–10. https://doi.org/10.1016/j.cccn.2005.05.012.PubMedView ArticleGoogle Scholar
  227. Tugnoli V, Tosi MR, Tinti A, Trinchero A, Bottura G, Fini G. Characterization of lipids from human brain tissues by multinuclear magnetic resonance spectroscopy. Biopolymers. 2001;62(6):297–306. https://doi.org/10.1002/bip.10005.PubMedView ArticleGoogle Scholar
  228. Tugnoli V, Bottura G, Fini G, Reggiani A, Tinti A, Trinchero A, et al. 1H-NMR and 13C-NMR lipid profiles of human renal tissues. Biopolymers. 2003;72(2):86–95. https://doi.org/10.1002/bip.10299.PubMedView ArticleGoogle Scholar
  229. Yates AJ, Thompson DK, Boesel CP, Albrightson C, Hart RW. Lipid composition of human neural tumors. J Lipid Res. 1979;20(4):428–36.PubMedGoogle Scholar
  230. Ohmoto T, Nishitsuji K, Yoshitani N, Mizuguchi M, Yanagisawa Y, Saito H, et al. K604, a specific acylCoA:cholesterol acyltransferase 1 inhibitor, suppresses proliferation of U251MG glioblastoma cells. Mol Med Rep. 2015;12(4):6037–42. https://doi.org/10.3892/mmr.2015.4200.PubMedView ArticleGoogle Scholar
  231. LaPensee CR, Mann JE, Rainey WE, Crudo V, Hunt SW 3rd, Hammer GD. ATR-101, a selective and potent inhibitor of Acyl-CoA acyltransferase 1, induces apoptosis in H295R adrenocortical cells and in the adrenal cortex of dogs. Endocrinology. 2016;157(5):1775–88. https://doi.org/10.1210/en.2015-2052.PubMedView ArticleGoogle Scholar
  232. Bemlih S, Poirier MD, El Andaloussi A. Acyl-coenzyme A: cholesterol acyltransferase inhibitor Avasimibe affect survival and proliferation of glioma tumor cell lines. Cancer Biol Ther. 2010;9(12):1025–32.PubMedView ArticleGoogle Scholar
  233. Stopsack KH, Gerke TA, Andren O, Andersson SO, Giovannucci EL, Mucci LA, et al. Cholesterol uptake and regulation in high-grade and lethal prostate cancers. Carcinogenesis. 2017;38(8):806–11. https://doi.org/10.1093/carcin/bgx058.PubMedView ArticlePubMed CentralGoogle Scholar
  234. Saraon P, Trudel D, Kron K, Dmitromanolakis A, Trachtenberg J, Bapat B, et al. Evaluation and prognostic significance of ACAT1 as a marker of prostate cancer progression. Prostate. 2014;74(4):372–80. https://doi.org/10.1002/pros.22758.PubMedView ArticleGoogle Scholar
  235. Li J, Gu D, Lee SS, Song B, Bandyopadhyay S, Chen S, et al. Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene. 2016;35(50):6378–88. https://doi.org/10.1038/onc.2016.168.PubMedPubMed CentralView ArticleGoogle Scholar
  236. Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest. 2006;116(3):607–14. https://doi.org/10.1172/JCI27883.PubMedPubMed CentralView ArticleGoogle Scholar
  237. Calkin AC, Tontonoz P. Liver x receptor signaling pathways and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30(8):1513–8. https://doi.org/10.1161/ATVBAHA.109.191197.PubMedView ArticleGoogle Scholar
  238. Zelcer N, Hong C, Boyadjian R, Tontonoz P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science. 2009;325(5936):100–4. https://doi.org/10.1126/science.1168974.PubMedPubMed CentralView ArticleGoogle Scholar
  239. Villa GR, Hulce JJ, Zanca C, Bi J, Ikegami S, Cahill GL, et al. An LXR-cholesterol axis creates a metabolic co-dependency for brain cancers. Cancer Cell. 2016;30(5):683–93. https://doi.org/10.1016/j.ccell.2016.09.008.PubMedPubMed CentralView ArticleGoogle Scholar
  240. Jakobsson T, Treuter E, Gustafsson JA, Steffensen KR. Liver X receptor biology and pharmacology: new pathways, challenges and opportunities. Trends Pharmacol Sci. 2012;33(7):394–404. https://doi.org/10.1016/j.tips.2012.03.013.PubMedView ArticleGoogle Scholar
  241. Wu Y, Yu DD, Yan DL, Hu Y, Chen D, Liu Y, et al. Liver X receptor as a drug target for the treatment of breast cancer. Anticancer Drugs. 2016;27(5):373–82. https://doi.org/10.1097/CAD.0000000000000348.PubMedView ArticleGoogle Scholar
  242. Flaveny CA, Griffett K, El-Gendy Bel D, Kazantzis M, Sengupta M, Amelio AL, et al. Broad Anti-tumor activity of a small molecule that selectively targets the Warburg effect and lipogenesis. Cancer Cell. 2015;28(1):42–56. https://doi.org/10.1016/j.ccell.2015.05.007.PubMedPubMed CentralView ArticleGoogle Scholar
  243. Gomes AS, Ramos H, Soares J, Saraiva L. p53 and glucose metabolism: an orchestra to be directed in cancer therapy. Pharmacol Res. 2018. https://doi.org/10.1016/j.phrs.2018.03.015.View ArticlePubMedGoogle Scholar
  244. Tarrado-Castellarnau M, de Atauri P, Cascante M. Oncogenic regulation of tumor metabolic reprogramming. Oncotarget. 2016;7(38):62726–53. https://doi.org/10.18632/oncotarget.10911.PubMedPubMed CentralView ArticleGoogle Scholar
  245. Jia D, Park JH, Jung KH, Levine H, Kaipparettu BA. Elucidating the metabolic plasticity of cancer: mitochondrial reprogramming and hybrid metabolic states. Cells. 2018. https://doi.org/10.3390/cells7030021.PubMedPubMed CentralView ArticleGoogle Scholar
  246. Corbet C, Feron O. Emerging roles of lipid metabolism in cancer progression. Curr Opin Clin Nutr Metab Care. 2017;20(4):254–60. https://doi.org/10.1097/MCO.0000000000000381.PubMedView ArticleGoogle Scholar
  247. Nakamura MT, Yudell BE, Loor JJ. Regulation of energy metabolism by long-chain fatty acids. Prog Lipid Res. 2014;53:124–44. https://doi.org/10.1016/j.plipres.2013.12.001.PubMedView ArticleGoogle Scholar
  248. Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest. 2010;120(1):142–56. https://doi.org/10.1172/JCI38942.PubMedView ArticleGoogle Scholar
  249. Tirado-Velez JM, Joumady I, Saez-Benito A, Cozar-Castellano I, Perdomo G. Inhibition of fatty acid metabolism reduces human myeloma cells proliferation. PLoS ONE. 2012;7(9):e46484. https://doi.org/10.1371/journal.pone.0046484.PubMedPubMed CentralView ArticleGoogle Scholar
  250. Liu PP, Liu J, Jiang WQ, Carew JS, Ogasawara MA, Pelicano H, et al. Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline. Oncogene. 2016;35(43):5663–73. https://doi.org/10.1038/onc.2016.103.PubMedPubMed CentralView ArticleGoogle Scholar
  251. Yadav RK, Singh M, Roy S, Ansari MN, Saeedan AS, Kaithwas G. Modulation of oxidative stress response by flaxseed oil: role of lipid peroxidation and underlying mechanisms. Prostaglandins Other Lipid Mediat. 2018;135:21–6. https://doi.org/10.1016/j.prostaglandins.2018.02.003.PubMedView ArticleGoogle Scholar
  252. Hao S, Liang B, Huang Q, Dong S, Wu Z, He W, et al. Metabolic networks in ferroptosis. Oncol Lett. 2018;15(4):5405–11. https://doi.org/10.3892/ol.2018.8066.PubMedPubMed CentralView ArticleGoogle Scholar
  253. Latunde-Dada GO. Ferroptosis: role of lipid peroxidation, iron and ferritinophagy. Biochim Biophys Acta. 2017;1861(8):1893–900. https://doi.org/10.1016/j.bbagen.2017.05.019.PubMedView ArticleGoogle Scholar
  254. Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochem Biophys Res Commun. 2017;482(3):419–25. https://doi.org/10.1016/j.bbrc.2016.10.086.PubMedPubMed CentralView ArticleGoogle Scholar
  255. Agmon E, Solon J, Bassereau P, Stockwell BR. Modeling the effects of lipid peroxidation during ferroptosis on membrane properties. Sci Rep. 2018;8(1):5155. https://doi.org/10.1038/s41598-018-23408-0.PubMedView ArticlePubMed CentralGoogle Scholar
  256. Agmon E, Stockwell BR. Lipid homeostasis and regulated cell death. Curr Opin Chem Biol. 2017;39:83–9. https://doi.org/10.1016/j.cbpa.2017.06.002.PubMedView ArticlePubMed CentralGoogle Scholar
  257. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26(3):165–76. https://doi.org/10.1016/j.tcb.2015.10.014.PubMedView ArticleGoogle Scholar
  258. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72. https://doi.org/10.1016/j.cell.2012.03.042.PubMedPubMed CentralView ArticleGoogle Scholar
  259. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1–2):317–31. https://doi.org/10.1016/j.cell.2013.12.010.PubMedPubMed CentralView ArticleGoogle Scholar
  260. Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016;12(7):497–503. https://doi.org/10.1038/nchembio.2079.PubMedPubMed CentralView ArticleGoogle Scholar
  261. Weiwer M, Bittker JA, Lewis TA, Shimada K, Yang WS, MacPherson L, et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett. 2012;22(4):1822–6. https://doi.org/10.1016/j.bmcl.2011.09.047.PubMedView ArticleGoogle Scholar
  262. Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15(3):234–45. https://doi.org/10.1016/j.chembiol.2008.02.010.PubMedPubMed CentralView ArticleGoogle Scholar
  263. Cheng CS, Wang Z, Chen J. Targeting FASN in breast cancer and the discovery of promising inhibitors from natural products derived from traditional Chinese medicine. Evid Based Complement Altern Med. 2014;2014:232946. https://doi.org/10.1155/2014/232946.View ArticleGoogle Scholar
  264. Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M, et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine. 2015;2(8):808–24. https://doi.org/10.1016/j.ebiom.2015.06.020.PubMedPubMed CentralView ArticleGoogle Scholar
  265. Zhou W, Han WF, Landree LE, Thupari JN, Pinn ML, Bililign T, et al. Fatty acid synthase inhibition activates AMP-activated protein kinase in SKOV3 human ovarian cancer cells. Cancer Res. 2007;67(7):2964–71. https://doi.org/10.1158/0008-5472.CAN-06-3439.PubMedView ArticleGoogle Scholar
  266. Orita H, Coulter J, Lemmon C, Tully E, Vadlamudi A, Medghalchi SM, et al. Selective inhibition of fatty acid synthase for lung cancer treatment. Clin Cancer Res. 2007;13(23):7139–45. https://doi.org/10.1158/1078-0432.CCR-07-1186.PubMedView ArticleGoogle Scholar
  267. Alli PM, Pinn ML, Jaffee EM, McFadden JM, Kuhajda FP. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene. 2005;24(1):39–46. https://doi.org/10.1038/sj.onc.1208174.PubMedView ArticleGoogle Scholar
  268. Sadowski MC, Pouwer RH, Gunter JH, Lubik AA, Quinn RJ, Nelson CC. The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer. Oncotarget. 2014;5(19):9362–81. https://doi.org/10.18632/oncotarget.2433.PubMedPubMed CentralView ArticleGoogle Scholar
  269. Lee HR, Hwang KA, Nam KH, Kim HC, Choi KC. Progression of breast cancer cells was enhanced by endocrine-disrupting chemicals, triclosan and octylphenol, via an estrogen receptor-dependent signaling pathway in cellular and mouse xenograft models. Chem Res Toxicol. 2014;27(5):834–42. https://doi.org/10.1021/tx5000156.PubMedView ArticleGoogle Scholar
  270. Pisanu ME, Noto A, De Vitis C, Morrone S, Scognamiglio G, Botti G, et al. Blockade of stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells. Cancer Lett. 2017;406:93–104. https://doi.org/10.1016/j.canlet.2017.07.027.PubMedView ArticleGoogle Scholar
  271. Ren XR, Wang J, Osada T, Mook RA Jr, Morse MA, Barak LS, et al. Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth. Breast Cancer Res. 2015;17:20. https://doi.org/10.1186/s13058-015-0528-9.PubMedPubMed CentralView ArticleGoogle Scholar
  272. Schlaepfer IR, Rider L, Rodrigues LU, Gijon MA, Pac CT, Romero L, et al. Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol Cancer Ther. 2014;13(10):2361–71. https://doi.org/10.1158/1535-7163.MCT-14-0183.PubMedPubMed CentralView ArticleGoogle Scholar
  273. Brown MS, Radhakrishnan A, Goldstein JL. Retrospective on cholesterol homeostasis: the central role of scap. Annu Rev Biochem. 2017. https://doi.org/10.1146/annurev-biochem-062917-011852.View ArticlePubMedGoogle Scholar
  274. Gao Y, Zhou Y, Goldstein JL, Brown MS, Radhakrishnan A. Cholesterol-induced conformational changes in the sterol-sensing domain of the Scap protein suggest feedback mechanism to control cholesterol synthesis. J Biol Chem. 2017;292(21):8729–37. https://doi.org/10.1074/jbc.M117.783894.PubMedView ArticlePubMed CentralGoogle Scholar

Copyright

© The Author(s) 2018

Advertisement

Cancer Communications

ISSN: 2523-3548

Contact us