Metformin directly alters key glycolytic enzyme protein expression and mitochondrial function in the endometria of PCOS patients

Abstract

Objectives: Polycystic ovary syndrome (PCOS) is a significant risk factor for the development and progression of type I endometrial cancer (EC). In a recent case study, we have reported a proof-of-concept that a combination of metformin and oral contraceptives treats earlystage EC in PCOS patients. Although metformin-induced metabolic effects in PCOS and EC patients have been investigated, it is not known whether this therapeutic drug has a direct effect on the endometria and further regulates glycolysis and mitochondrial function in PCOS patients with endometrial hyperplasia and carcinoma. Method(s): Western blot analysis was used in this study. Result(s): Weshow that endometria from PCOS patients with endometrial hyperplasia and carcinoma have a distinct protein expression pattern of glycolytic enzymes, including mitochondrial TFAM, which is necessary for energy production from oxidative phosphorylation. Using endometrial tissues from PCOS patients with hyperplasia, we evaluated the effects of metformin on the protein levels of key enzymes in glycolysis in vitro. In response to metformin treatment, HK2 expression was decreased, whereas PFK, PKM2, and LDHA expression was increased compared to controls. Interestingly, the expression of TFAM and cleaved caspase-3, a downstream target of cytochrome C, was increased after metformin treatment. Conclusion(s): Overall, our data indicate that metformin integrates endometrial glycolytic metabolism with mitochondria-related cellular function by regulating key glycolytic enzyme protein expression in the endometrium.