title: Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells.
abstract: 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 10μM metformin combined with 1μM 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.
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Xie
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.forename: Qian
authors.initials: Q
authors.lastname: Hu
authors.forename: Lei
authors.initials: L
authors.lastname: Ji
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qin-Ping
authors.initials: QP
authors.lastname: Liao
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017258:Medroxyprogesterone Acetate; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D008954:Models, Biological; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D007004:Hypoglycemic Agents; D011980:Receptors, Progesterone; D008687:Metformin; D017258:Medroxyprogesterone Acetate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases