title: Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway.
abstract: The induction of senescence for cancer treatment has provoked considerable interest recently. Metformin, a first-line drug for diabetes mellitus type 2, appears to be associated with a lower risk and improved outcomes in hepatocellular carcinoma (HCC). The mechanism involved in function of metformin in HCC is poorly understood. We show that low doses of metformin induced hepatoma cell senescence characterized by accumulation of senescence-associated β-galactosidase activity (SA-β-gal) and the senescence marker Dec1, whereas the higher doses initiated apoptotic cell death. Metformin-induced senescence was accompanied by enhanced phosphorylation levels of AMP-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase (ACC). The expression of acetylated p53 at Lys382 (Ac-p53) and p21 was also increased, while phosphorylation of p53 at Ser15 (p-p53), p53, p16 and pRB was rarely altered after metformin treatment. Moreover, inhibition of AMPK decreased p-AMPK, p-ACC, Ac-p53 and p21 expression, diminished SA-β-gal staining and restored hepatoma cell proliferation. In addition, p53 siRNA transfection attenuated metformin-induced SA-β-gal staining. Intriguingly, co-expression of SIRT1 and p53 dramatically reduced the levels of Ac-p53, however, low doses of metformin treatment partially reversed the effect of SIRT1 on p53 acetylation and elevated SA-β-gal activity. These observations indicate that activation of the AMPK pathway promotes senescence in hepatoma cells exposed to low concentrations of metformin in a p53-dependent manner. Further, low doses of metformin may have the potential to be used as an adjuvant to HCC therapy.
authors: Department of Intensive Care Unit, Affiliated Tumor Hospital of Guangzhou Medical University, Guangzhou 510095, Guangdong, P.R. China.
authors: Gao
authors: G
authors: Yi
authors: Zhimin
authors: Z
authors: He
authors: Xinke
authors: X
authors: Zhou
authors: Lewu
authors: L
authors: Xian
authors: Taize
authors: T
authors: Yuan
authors: Xiaoting
authors: X
authors: Jia
authors: Jian
authors: J
authors: Hong
authors: Lu
authors: L
authors: He
authors: Jifang
authors: J
authors: Liu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008687:Metformin; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases