- Gynecol Oncol. 2009 Oct 10.
Metformin is a potent inhibitor of endometrial cancer cell proliferation-implications for a novel treatment strategy.
Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL.
of Gynecologic Oncology, Department of Obstetrics and Gynecology,
University of North Carolina at Chapel Hill, CB #7572, Chapel Hill, NC
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.
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
real-time RT-PCR. Western immunoblotting was performed to determine the
expression of the downstream targets of 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 h 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.