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.

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

“…Yi et al demonstrated that a low concentration of metformin induced p53-dependent senescence in hepatoma cells, whereas higher doses induced apoptotic cell death in these cells. 24 Our observation that metformin administration restrained the growth of xenograft tumors in BALB/c nude mice is in line with a previous report that metformin treatment decreased tumorigenic potential. 25 Further investigation of the mechanisms underlying metformin's antitumor effect in prostate cancer revealed that metformin increased PEDF expression in both prostate cancer cells and tumor tissue.…”

Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment

“…81 Low concentration of metformin was reported to induce a p53-dependent senescence in HCC cells via activation of the AMPK pathway. 82 Nonetheless, metformin also protected endothelial cells from hyperglycemia-induced senescence in mouse microvascular 83 So, the role of metformin in cell senescence remains unresolved. In addition, metformin can target cancer stem cells.…”

6-Gingerol inhibits osteosarcoma cell proliferation through apoptosis and AMPK activation

“…In addition, the activation of AMPK has been reported to inhibit the growth of different carcinoma cells such as hepatocarcinoma cell HepG2 and colorectal cancer cell SW620 [8,9]. Recent studies find that genetic manipulation of the AMPK upstream activator LKB1 is crucial for hepatoma development and activated AMPK inhibits hepatoma growth by destabilizing p53 in a SIRT1-dependent manner [10]. These findings provide evidence that AMPK may serve as a potential anti-tumor target for treating different carcinomas.…”