Kohler P. The strategies of energy conservation in helminths. Mol Biochem Parasitol. 1985;17(1):1–18.
Article
CAS
PubMed
Google Scholar
Yang C, Sudderth J, Dang T, Bachoo RM, McDonald JG, DeBerardinis RJ. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res. 2009;69(20):7986–93. https://doi.org/10.1158/0008-5472.CAN-09-2266.
CAS
PubMed
PubMed Central
Google Scholar
Yang C, Ko B, Hensley CT, Jiang L, Wasti AT, Kim J, et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell. 2014;56(3):414–24. https://doi.org/10.1016/j.molcel.2014.09.025.
CAS
PubMed
PubMed Central
Google Scholar
Vacanti NM, Divakaruni AS, Green CR, Parker SJ, Henry RR, Ciaraldi TP, et al. Regulation of substrate utilization by the mitochondrial pyruvate carrier. Mol Cell. 2014;56(3):425–35. https://doi.org/10.1016/j.molcel.2014.09.024.
CAS
PubMed
PubMed Central
Google Scholar
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23(1):27–47. https://doi.org/10.1016/j.cmet.2015.12.006.
CAS
PubMed
PubMed Central
Google Scholar
Tian Y, Du W, Cao S, Wu Y, Dong N, Wang Y, et al. Systematic analyses of glutamine and glutamate metabolisms across different cancer types. Chin J Cancer. 2017;36(1):88. https://doi.org/10.1186/s40880-017-0255-y.
PubMed
PubMed Central
Google Scholar
Narta UK, Kanwar SS, Azmi W. Pharmacological and clinical evaluation of l-asparaginase in the treatment of leukemia. Crit Rev Oncol Hematol. 2007;61(3):208–21. https://doi.org/10.1016/j.critrevonc.2006.07.009.
PubMed
Google Scholar
Chio IIC, Tuveson DA. ROS in cancer: the burning question. Trends Mol Med. 2017;23(5):411–29. https://doi.org/10.1016/j.molmed.2017.03.004.
CAS
PubMed
Google Scholar
Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, et al. The cystine/glutamate antiporter system x(c)(−) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal. 2013;18(5):522–55. https://doi.org/10.1089/ars.2011.4391.
CAS
PubMed
PubMed Central
Google Scholar
Conrad M, Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system x(c)(−): cystine supplier and beyond. Amino Acids. 2012;42(1):231–46. https://doi.org/10.1007/s00726-011-0867-5.
CAS
PubMed
Google Scholar
Lo M, Wang YZ, Gout PW. The x(c)− cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol. 2008;215(3):593–602. https://doi.org/10.1002/jcp.21366.
CAS
PubMed
Google Scholar
Bannai S. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem. 1986;261(5):2256–63.
CAS
PubMed
Google Scholar
Sato H, Tamba M, Ishii T, Bannai S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem. 1999;274(17):11455–8.
Article
CAS
PubMed
Google Scholar
Nakamura E, Sato M, Yang H, Miyagawa F, Harasaki M, Tomita K, et al. 4F2 (CD98) heavy chain is associated covalently with an amino acid transporter and controls intracellular trafficking and membrane topology of 4F2 heterodimer. J Biol Chem. 1999;274(5):3009–16.
Article
CAS
PubMed
Google Scholar
Shin CS, Mishra P, Watrous JD, Carelli V, D’Aurelio M, Jain M, et al. The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility. Nat Commun. 2017;8:15074. https://doi.org/10.1038/ncomms15074.
PubMed
PubMed Central
Google Scholar
Stipanuk MH. Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr. 2004;24:539–77. https://doi.org/10.1146/annurev.nutr.24.012003.132418.
CAS
PubMed
Google Scholar
Zhang W, Trachootham D, Liu J, Chen G, Pelicano H, Garcia-Prieto C, et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat Cell Biol. 2012;14(3):276–86. https://doi.org/10.1038/ncb2432.
CAS
PubMed
PubMed Central
Google Scholar
Lu SC. Regulation of glutathione synthesis. Mol Aspects Med. 2009;30(1–2):42–59. https://doi.org/10.1016/j.mam.2008.05.005.
CAS
PubMed
Google Scholar
Rossier G, Meier C, Bauch C, Summa V, Sordat B, Verrey F, et al. LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem. 1999;274(49):34948–54.
Article
CAS
PubMed
Google Scholar
Ohno H, Nakatsu Y, Sakoda H, Kushiyama A, Ono H, Fujishiro M, et al. 4F2hc stabilizes GLUT1 protein and increases glucose transport activity. Am J Physiol Cell Physiol. 2011;300(5):C1047–54. https://doi.org/10.1152/ajpcell.00416.2010.
CAS
PubMed
Google Scholar
Pineda M, Fernandez E, Torrents D, Estevez R, Lopez C, Camps M, et al. Identification of a membrane protein, LAT-2, that co-expresses with 4F2 heavy chain, an l-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem. 1999;274(28):19738–44.
Article
CAS
PubMed
Google Scholar
Bannai S, Tateishi N. Role of membrane transport in metabolism and function of glutathione in mammals. J Membr Biol. 1986;89(1):1–8.
Article
CAS
PubMed
Google Scholar
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–85. https://doi.org/10.1016/j.cell.2017.09.021.
CAS
PubMed
Google Scholar
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.
CAS
PubMed
PubMed Central
Google Scholar
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.
CAS
PubMed
PubMed Central
Google Scholar
Lewerenz J, Sato H, Albrecht P, Henke N, Noack R, Methner A, et al. Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression. Cell Death Differ. 2012;19(5):847–58. https://doi.org/10.1038/cdd.2011.165.
CAS
PubMed
Google Scholar
Shih AY, Erb H, Sun X, Toda S, Kalivas PW, Murphy TH. Cystine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation. J Neurosci. 2006;26(41):10514–23. https://doi.org/10.1523/JNEUROSCI.3178-06.2006.
CAS
PubMed
Google Scholar
Banjac A, Perisic T, Sato H, Seiler A, Bannai S, Weiss N, et al. The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene. 2008;27(11):1618–28. https://doi.org/10.1038/sj.onc.1210796.
CAS
PubMed
Google Scholar
Polewski MD, Reveron-Thornton RF, Cherryholmes GA, Marinov GK, Cassady K, Aboody KS. Increased expression of system xc− in glioblastoma confers an altered metabolic state and temozolomide resistance. Mol Cancer Res. 2016;14(12):1229–42. https://doi.org/10.1158/1541-7786.MCR-16-0028.
CAS
PubMed
Google Scholar
Okuno S, Sato H, Kuriyama-Matsumura K, Tamba M, Wang H, Sohda S, et al. Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines. Br J Cancer. 2003;88(6):951–6. https://doi.org/10.1038/sj.bjc.6600786.
CAS
PubMed
PubMed Central
Google Scholar
Ye P, Mimura J, Okada T, Sato H, Liu T, Maruyama A, et al. Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. Mol Cell Biol. 2014;34(18):3421–34. https://doi.org/10.1128/MCB.00221-14.
PubMed
PubMed Central
Google Scholar
Koppula P, Zhang Y, Shi J, Li W, Gan B. The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. J Biol Chem. 2017;292(34):14240–9. https://doi.org/10.1074/jbc.M117.798405.
CAS
PubMed
Google Scholar
Goji T, Takahara K, Negishi M, Katoh H. Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation. J Biol Chem. 2017;292(48):19721–32. https://doi.org/10.1074/jbc.M117.814392.
CAS
PubMed
Google Scholar
Spitz DR, Sim JE, Ridnour LA, Galoforo SS, Lee YJ. Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism? Ann NY Acad Sci. 2000;899:349–62.
Article
CAS
PubMed
Google Scholar
Ahmad IM, Aykin-Burns N, Sim JE, Walsh SA, Higashikubo R, Buettner GR, et al. Mitochondrial O2*− and H2O2 mediate glucose deprivation-induced stress in human cancer cells. J Biol Chem. 2005;280(6):4254–63. https://doi.org/10.1074/jbc.M411662200.
CAS
PubMed
Google Scholar
Dai F, Lee H, Zhang Y, Zhuang L, Yao H, Xi Y, et al. BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response. Proc Natl Acad Sci USA. 2017;114(12):3192–7. https://doi.org/10.1073/pnas.1619588114.
CAS
PubMed
PubMed Central
Google Scholar
Bannai S, Ishii T. A novel function of glutamine in cell culture: utilization of glutamine for the uptake of cystine in human fibroblasts. J Cell Physiol. 1988;137(2):360–6. https://doi.org/10.1002/jcp.1041370221.
CAS
PubMed
Google Scholar
Timmerman LA, Holton T, Yuneva M, Louie RJ, Padro M, Daemen A, et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell. 2013;24(4):450–65. https://doi.org/10.1016/j.ccr.2013.08.020.
CAS
PubMed
PubMed Central
Google Scholar
Muir A, Danai LV, Gui DY, Waingarten CY, Lewis CA, Vander Heiden MG. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. Elife. 2017. https://doi.org/10.7554/elife.27713.
Google Scholar
Curthoys NP, Watford M. Regulation of glutaminase activity and glutamine metabolism. Annu Rev Nutr. 1995;15:133–59. https://doi.org/10.1146/annurev.nu.15.070195.001025.
CAS
PubMed
Google Scholar
Bannai S. Induction of cystine and glutamate transport activity in human fibroblasts by diethyl maleate and other electrophilic agents. J Biol Chem. 1984;259(4):2435–40.
CAS
PubMed
Google Scholar
Bannai S, Kitamura E. Adaptive enhancement of cystine and glutamate uptake in human diploid fibroblasts in culture. Biochim Biophys Acta. 1982;721(1):1–10.
Article
CAS
PubMed
Google Scholar
Bannai S, Sato H, Ishii T, Taketani S. Enhancement of glutathione levels in mouse peritoneal macrophages by sodium arsenite, cadmium chloride and glucose/glucose oxidase. Biochim Biophys Acta. 1991;1092(2):175–9.
Article
CAS
PubMed
Google Scholar
Sato H, Nomura S, Maebara K, Sato K, Tamba M, Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Biochem Biophys Res Commun. 2004;325(1):109–16. https://doi.org/10.1016/j.bbrc.2004.10.009.
CAS
PubMed
Google Scholar
Sasaki H, Sato H, Kuriyama-Matsumura K, Sato K, Maebara K, Wang H, et al. Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J Biol Chem. 2002;277(47):44765–71. https://doi.org/10.1074/jbc.M208704200.
CAS
PubMed
Google Scholar
Sykiotis GP, Bohmann D. Stress-activated cap’n’collar transcription factors in aging and human disease. Sci Signal. 2010;3(112):re3. https://doi.org/10.1126/scisignal.3112re3.
PubMed
PubMed Central
Google Scholar
Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, et al. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci. 2003;23(8):3394–406.
Article
CAS
PubMed
Google Scholar
Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17(10):1374–95. https://doi.org/10.15252/embr.201642195.
CAS
PubMed
PubMed Central
Google Scholar
Kilberg MS, Shan J, Su N. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol Metab. 2009;20(9):436–43. https://doi.org/10.1016/j.tem.2009.05.008.
CAS
PubMed
PubMed Central
Google Scholar
Lewerenz J, Maher P. Basal levels of eIF2alpha phosphorylation determine cellular antioxidant status by regulating ATF4 and xCT expression. J Biol Chem. 2009;284(2):1106–15. https://doi.org/10.1074/jbc.M807325200.
CAS
PubMed
PubMed Central
Google Scholar
Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520(7545):57–62. https://doi.org/10.1038/nature14344.
CAS
PubMed
PubMed Central
Google Scholar
Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63(1):173–84. https://doi.org/10.1002/hep.28251.
CAS
PubMed
Google Scholar
Roh JL, Kim EH, Jang H, Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol. 2017;11:254–62. https://doi.org/10.1016/j.redox.2016.12.010.
CAS
PubMed
Google Scholar
Fan Z, Wirth AK, Chen D, Wruck CJ, Rauh M, Buchfelder M, et al. Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis. 2017;6(8):e371. https://doi.org/10.1038/oncsis.2017.65.
CAS
PubMed
PubMed Central
Google Scholar
Chen D, Fan Z, Rauh M, Buchfelder M, Eyupoglu IY, Savaskan N. ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. Oncogene. 2017;36(40):5593–608. https://doi.org/10.1038/onc.2017.146.
CAS
PubMed
PubMed Central
Google Scholar
Chen D, Rauh M, Buchfelder M, Eyupoglu IY, Savaskan N. The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas. Oncotarget. 2017;8(31):51164–76. https://doi.org/10.18632/oncotarget.17737.
PubMed
PubMed Central
Google Scholar
Furfaro AL, Piras S, Domenicotti C, Fenoglio D, De Luigi A, Salmona M, et al. Role of Nrf2, HO-1 and GSH in neuroblastoma cell resistance to bortezomib. PLoS ONE. 2016;11(3):e0152465. https://doi.org/10.1371/journal.pone.0152465.
CAS
PubMed
PubMed Central
Google Scholar
Sayin VI, LeBoeuf SE, Singh SX, Davidson SM, Biancur D, Guzelhan BS, et al. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. Elife. 2017. https://doi.org/10.7554/elife.28083.
PubMed
PubMed Central
Google Scholar
Chang YF, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem. 2007;76:51–74. https://doi.org/10.1146/annurev.biochem.76.050106.093909.
CAS
PubMed
Google Scholar
Martin L, Gardner LB. Stress-induced inhibition of nonsense-mediated RNA decay regulates intracellular cystine transport and intracellular glutathione through regulation of the cystine/glutamate exchanger SLC7A11. Oncogene. 2015;34(32):4211–8. https://doi.org/10.1038/onc.2014.352.
CAS
PubMed
Google Scholar
Liu XX, Li XJ, Zhang B, Liang YJ, Zhou CX, Cao DX, et al. MicroRNA-26b is under expressed in human breast cancer and induces cell apoptosis by targeting SLC7A11. FEBS Lett. 2011;585(9):1363–7. https://doi.org/10.1016/j.febslet.2011.04.018.
CAS
PubMed
Google Scholar
Wu Y, Sun X, Song B, Qiu X, Zhao J. MiR-375/SLC7A11 axis regulates oral squamous cell carcinoma proliferation and invasion. Cancer Med. 2017;6(7):1686–97. https://doi.org/10.1002/cam4.1110.
CAS
PubMed
PubMed Central
Google Scholar
Drayton RM, Dudziec E, Peter S, Bertz S, Hartmann A, Bryant HE, et al. Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11. Clin Cancer Res. 2014;20(7):1990–2000. https://doi.org/10.1158/1078-0432.CCR-13-2805.
CAS
PubMed
PubMed Central
Google Scholar
Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(−) and thereby promotes tumor growth. Cancer Cell. 2011;19(3):387–400. https://doi.org/10.1016/j.ccr.2011.01.038.
CAS
PubMed
Google Scholar
Gu Y, Albuquerque CP, Braas D, Zhang W, Villa GR, Bi J, et al. mTORC2 regulates amino acid metabolism in cancer by phosphorylation of the cystine-glutamate antiporter xCT. Mol Cell. 2017;67(1):128–38. https://doi.org/10.1016/j.molcel.2017.05.030.
CAS
PubMed
Google Scholar
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;169(2):361–71. https://doi.org/10.1016/j.cell.2017.03.035.
CAS
PubMed
Google Scholar
Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496(7443):101–5. https://doi.org/10.1038/nature12040.
CAS
PubMed
PubMed Central
Google Scholar
Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17(4):351–9. https://doi.org/10.1038/ncb3124.
CAS
PubMed
PubMed Central
Google Scholar
Sato H, Shiiya A, Kimata M, Maebara K, Tamba M, Sakakura Y, et al. Redox imbalance in cystine/glutamate transporter-deficient mice. J Biol Chem. 2005;280(45):37423–9. https://doi.org/10.1074/jbc.M506439200.
CAS
PubMed
Google Scholar
Bassi MT, Gasol E, Manzoni M, Pineda M, Riboni M, Martin R, et al. Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc. Pflugers Arch. 2001;442(2):286–96.
Article
CAS
PubMed
Google Scholar
Kim JY, Kanai Y, Chairoungdua A, Cha SH, Matsuo H, Kim DK, et al. Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. Biochim Biophys Acta. 2001;1512(2):335–44.
Article
CAS
PubMed
Google Scholar
Burdo J, Dargusch R, Schubert D. Distribution of the cystine/glutamate antiporter system xc− in the brain, kidney, and duodenum. J Histochem Cytochem. 2006;54(5):549–57. https://doi.org/10.1369/jhc.5A6840.2006.
CAS
PubMed
Google Scholar
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.
CAS
PubMed
Google Scholar
Gout PW, Buckley AR, Simms CR, Bruchovsky N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)− cystine transporter: a new action for an old drug. Leukemia. 2001;15(10):1633–40.
Article
CAS
PubMed
Google Scholar
Romero R, Sayin VI, Davidson SM, Bauer MR, Singh SX, LeBoeuf SE, et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med. 2017. https://doi.org/10.1038/nm.4407.
PubMed
PubMed Central
Google Scholar