Metformin inhibits the proliferation in EOC (epithelial ovarian cancer) mediated by AMPK/mTOR signaling pathway in vitro

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer and accounts for the fifth most common cause of cancer-related deaths in women. Initial treatment with surgery and chemotherapy has improved survival significantly. However, most patients relapse within 2 years and develop chemoresistance. Thus, it is urgent to develop more effective treatment strategies. Metformin is a first-line anti-diabetic drug, but also be found its promising anti-cancer effect in many solid tumors. This study was attempted to evaluate the effect and mechanism of metformin in epithelial ovarian cancer cells. Cells were treated with metformin at different doses and different time intervals. The proliferation ability of cells was analyzed by cell counting kit-8 (CCK-8). Glucose uptake and secretion of lactic acid were measured in the culture medium by ELISA. Glycolysis key enzymes: Hexokinase 2 (HK 2) and Lactate dehydrogenase-A (LDHA) were detected by RT-qPCR. The activation of AMPK/mTOR signaling pathway and the concentration of ATP were evaluated in cell lysates. Metformin inhibited cell proliferation on both dose-dependent manner and time-dependent manner in SKOV3 cells. Metformin increased glucose uptake, lactic acid secretion and the expression of HK 2 and LDHA, but decreased the production of ATP. Both AICAR (1 mM) and metformin (20 mM) enhanced the AMPK/mTOR signaling and glycolysis, but compound C (15 μM) could reverse these effects. These data suggest that metformin might inhibit the proliferation in ovarian cancer cells by modulating the AMPK/mTOR signaling pathway, which also indicate the chemotherapeutic potential of metformin in epithelial ovarian cancer.