Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells

Progesterone has been used in the hormonal treatment of endometrial cancer (EC) for many years, but the response rates are unsatisfying. The down-regulated progesterone receptor (PR) is the main reason for treatment failure. The insulin-like growth factor (IGF) system is related to EC risk, and IGF-I can inhibit PR transcription in breast cancer. Recent evidence suggests that metformin-combined oral contraceptives may reverse progesterone-resistant atypical endometrial hyperplasia, but the mechanism is unclear. We attempt to investigate the interaction of metformin, PR and IGF-II expression, and identify whether metformin can enhance the antitumor effect of medroxyprogesterone acetate (MPA) using Ishikawa and HEC-1B EC cell lines. We found that both IGF-I and IGF-II inhibit PR A/B mRNA and protein expression, whereas metformin markedly promotes PR expression. In parallel, IGF-II increases phosphorylation of AKT and p70S6K, while metformin increases AMPK phosphorylation and decreases p70S6K phosphorylation. The effects of metformin on PR A/B and p70S6K are partially reversed by an AMPK inhibitor. Furthermore, metformin synergistically antiproliferates MPA in two cell lines, with the peak synergy occurring with 10 μM metformin combined with 1 μM MPA (CI = 0.20448 for Ishikawa, CI = 0.12801 for HEC-1B). Our results demonstrate that metformin promotes PR expression, which can be inhibited by overexpressed IGF-II in EC. This effect is partially mediated through activating AMPK followed by inhibiting the overactivated mTOR pathway.

► Metformin promotes PR expression via AMPK activation, which is followed by mTOR pathway inhibition in endometrial cancer.
► IGF-I and IGF-II inhibit PR expression via mTOR pathway activation.
► Metformin has a synergistic antitumor effect with MPA in endometrial cancer cells.
► MPA combined with metformin may be a novel treatment strategy in endometrial cancer.