Abstract
Metformin is a widely used first-line drug for treatment of type 2 diabetes mellitus. In recent years, it has been reported that administration of metformin can reduce carcinogenic risk and inhibit proliferation of cancer cells including those from glioma and breast cancer. The underlying mechanism is thought to involve increased LKB-1 phosphorylation induced by metformin, followed by LKB-1 phosphorylation and activation of AMP-activated protein kinase (AMPK), which then inhibits the mammalian target of rapamycin (mTOR) pathway and results in inhibition of cell proliferation. In endometrial cancer, metformin causes cell cycle arrest in vitro, reduces hTERT mRNA, inhibits the mTOR pathway via AMPK, and is involved in inhibition of phosphorylation of S6 ribosomal protein (S6RP). Metformin promotes expression of progesterone receptor by an action opposite to that of insulin-like growth factor-2 (IGF-2) when used in combination with medroxyprogesterone acetate. This enhances the antitumor effect and this approach may be applicable in a clinical setting.
Highlights
Metformin is a biguanide drug used for treatment of type 2 diabetes mellitus
The underlying mechanism is thought to involve increased LKB-1 phosphorylation induced by metformin, followed by LKB-1 phosphorylation and activation of AMP-activated protein kinase (AMPK), which inhibits the mammalian target of rapamycin pathway and results in inhibition of cell proliferation
ECC-1 and Ishikawa are both PTEN-positive cell lines, and these results show that metformin inhibits the mammalian target of rapamycin (mTOR) pathway via AMPK in cells with normal PTEN, which are especially common in type 2 endometrial cancer
Summary
Metformin is a biguanide drug used for treatment of type 2 diabetes mellitus. Long-term administration of metformin has been found to reduce carcinogenic risk for cancers derived from various tissues. Inhibition of cellular proliferation by metformin has been reported for glioma, colon cancer, and breast cancer. Activation of AMPK and inhibition of mTOR are thought to be key events in the anti-tumor effect of metformin and. Since endometrial cancer is commonly and intimately related to obesity, type 2 diabetes, and insulin resistance, the inherent action of metformin on metabolic regulation may improve the prognosis of patients with this cancer, and metformin may have direct antitumor effects at the cellular level, to those for other tumors. The effects of metformin on various cancers are discussed, with a focus on potential clinical application in treatment of endometrial cancer
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