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.

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UPSC and CC are managed similarly since sufficient data to separate treatment recommendations are lacking. Because both histologies are associated with a high rate of recurrence, adjuvant therapy is recommended even in women with early-stage disease. The remaining cell types should be treated similar to endometrioid or other low-grade histologies.

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