Metformin is a potent inhibitor of endometrial cancer cell proliferation—implications for a novel treatment strategy

Abstract

Objectives-Obesity and diabetes are strong risk factors that drive the development of type I endometrial cancers. Recent epidemiological evidence suggests that metformin may lower cancer risk and reduce rates of cancer deaths among diabetic patients. In order to better understand metformin's anti-tumorigenic potential, our goal was to assess the effect of metformin on proliferation and expression of key targets of metformin cell signaling in endometrial cancer cell lines.Methods-The endometrial cancer cell lines, ECC-1 and Ishikawa, were used. Cell proliferation was assessed after exposure to metformin. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by ELISA for caspase-3 activity. hTERT expression was determined by realtime RT-PCR. Western immunoblotting was performed to determine the expression of the downstream targets of metformin.Results-Metformin potently inhibited growth in a dose-dependent manner in both cell lines (IC 50 of 1 mM). Treatment with metformin resulted in G1 arrest, induction of apoptosis and decreased hTERT expression. Western immunoblot analysis demonstrated that metformin induced phosphorylation of AMPK, its immediate downstream mediator, within 24 hours of exposure. In parallel, treatment with metformin decreased phosphorylation of S6 protein, a key target of the mTOR pathway.Conclusions-We find that metformin is a potent inhibitor of cell proliferation in endometrial cancer cell lines. This effect is partially mediated through AMPK activation and subsequent inhibition of the mTOR pathway. This work should provide the scientific foundation for future investigation of metformin as a strategy for endometrial cancer prevention and treatment.

Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer

“…Evidence for a proapoptotic effect of metformin is mixed. Cantrell et al 22,28 showed that metformin promoted apoptosis in endometrial carcinoma cells whereas others have been unable to ) or combined metformin and bicalutamide. Using Student's t testing at individual time points revealed significantly reduced tumour growth in the combination group compared with all other groups at days 25 and 27 (*Po0.05).…”

“…Other studies have shown that the proapoptotic effect of metformin is only seen when high doses of the drug are utilized. 22 The in vitro model used in these studies did not assess the potential indirect effects of metformin that is, those mediated by inhibition of hyperinsulinaemia. This was more easily assessed using our in vivo xenograft model.…”

Metformin inhibits growth of eutopic stromal cells from adenomyotic endometrium via AMPK activation and subsequent inhibition of AKT phosphorylation: a possible role in the treatment of adenomyosis

“…Metformin is a biguanide drug that is widely used as a first-line pharmacological treatment in patients with type 2 diabetes (Cantrell et al 2010). Metformin exerts its effects through the activation of AMPK in muscle, adipose tissue, and liver (Towler & Hardie 2007).…”

Metformin: Hype or Hope for Cancer

“…37 Preclinical studies show that metformin inhibits endometrial, ovarian and glioma cells. 34,38,39 Metformin also causes decreased hepatocellular cancer incidence in diabetic patients. 40 In hepatocellular cancer cells, metformin was found to decrease mitochondrial oxygen consumption and suppress hypoxia induced HIF-1 alpha accumulation which was shown to be involved in the development of hepatocellular cancer.…”