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Table 1 Metformin targets multiple signaling pathways in cancer

From: Metformin targets multiple signaling pathways in cancer

Proposed mechanism Functions Tumor type/model References
AMPK-dependent Inhibition of cell mitosis and proliferation Human carcinoma tissues and human cancer cell lines [29]
Up-regulation of the p53–p21 axis and down-regulation of cyclin D1 T-cell acute lymphoblastic leukemia [3032]
DNA synthesis Pancreatic cancer [34]
Growth inhibition and G0/G1 cell cycle arrest Lymphoma cells [36]
Cell apoptosis Acute lymphoblastic leukemia [36]
Suppression of multidrug resistance 1 gene activation Breast cancer [37]
AMPK-independent REDD1, a negative regulator of mTOR, mediates cell cycle arrest and cyclin D1 decrease Prostate cancer cells [39]
Induced apoptosis Human ovarian cancer cells [40]
Suppression of mTOR Inhibition of global protein synthesis and cell proliferation Breast cancer [5456]
Repression of oncogenic mRNA translation Leukemia [30, 32]
Lung cancer [59, 60]
Inhibition of cell growth and induction of apoptosis Breast cancer [61, 62]
Prevents the development of carcinogen-induced premalignant lesions Oral squamous cell carcinoma [63]
Induction of autophagy Lymphoma [36]
Inhibits growth and decreases resistance to anoikis Thyroid cancer [35, 64]
Inhibits skin tumor promotion In overweight and obese mice with papilloma and squamous cell carcinoma [65]
Suppresses HER2 oncoprotein overexpression Breast cancer [101]
Suppression of IGF signaling Prevents androgen-mediated IGF-1R up-regulation; reduces cell proliferation, invasion, and clonogenic capacity Prostate cancer cells [82]
Reduces the circulating levels of insulin and IGF-1; blocks cell growth and proliferation A tobacco carcinogen-induced lung cancer model in A/J mice [60]
AMPK-induced phosphorylation of insulin receptor substrate-1 Switches off IGF-1-induced activation of Akt/Tsc1/mTOR Human pancreatic cancer cells, breast cancer cells [8385]
Activation of AMPK Disruption of crosstalk between insulin/IGF-1R and GPCR signaling Pancreatic cancer [86]
Activation of the JNK/p38 MAPK pathway Apoptosis-mediated effect Lung cancer cells [100]
The MAPK signaling pathway Synergistic effects of metformin in combination with gefitinib Lung cancer [59, 91]
Blocks tumor cells migration and invasion and inhibits MMP-9 activation Human fibrosarcoma [92]
Inhibits cell growth and colony formation and induces cell cycle arrest Breast cancer [9396]
Blocks survival signals Prostate cancer [97]
Endometrial cancer [98]
Inhibition of the NF-κB pathway Halts proliferation of cancer cells and causes death; sensitizes to chemotherapeutic reagents Inflammation-associated tumors [107]
Repression of the NF-κB and mTOR signaling pathways Growth inhibition Cutaneous squamous cell carcinoma [99]
Inhibition of CSCs Inhibits cellular transformation and selectively kills cancer stem cells Preclinical breast cancer models [119]
Down-regulation of CSC markers Inhibits cell proliferation, migration, and invasion Pancreatic cancer [121, 122]
Targeting CSCs and mTOR Inhibits esophageal cancer cell growth and sensitizes cells to 5-FU cytotoxic effects Esophageal cancer cells [123]
Selective suppression of NF-κB nuclear localization and STAT3 activity Inhibits nuclear translocation of NF-κB and phosphorylation of STAT3 in CSCs Breast cancer, prostate cancer, and melanoma cell lines [126]
  1. AMPK adenosine monophosphate-activated protein kinase, REDD1 regulated in development and DNA damage 1, mTOR mammalian target of rapamycin, HER2 human epidermal growth factor receptor-2, IGF insulin-like growth factor, GPCR G protein-coupled receptor, IGF-1 insulin-like growth factor-1, JNK c-Jun N-terminal kinase, MAPK mitogen-activated protein kinase, MMP-9 matrix metallopeptidase-9, NF-κB nuclear factor kappaB, CSCs cancer stem cells, 5-FU 5-fluorouracil, STAT3 signal transducer and activator of transcription 3