Introduction: Endometriosis is a chronic, hormone-dependent disorder characterized by the establishment and growth of endometrial tissue in extra-uterine sites, typically within the peritoneal cavity and causes debilitating pain. We have shown that peritoneal mesothelial cells recovered from the women with endometriosis have an altered energy metabolism with increased biosynthesis of lactate as a result of increased aerobic glycolysis. We hypothesize that ectopic endometrial tissue may use the excess lactate produced by peritoneal mesothelial cells as an energy source enhancing both their establishment and growth as endometriosis lesions and by targeting lactate metabolism endometriosis may be resolved.
Methods: Eutopic endometrium, endometriotic lesions, peritoneum (from sites distal and adjacent to the endometriosis lesion) and primary human peritoneal mesothelial cells (HPMCs) were collected with informed consent from women with or without endometriosis. Expression of lactate transporters were analysed in tissue biopsies (n=5) by qRT-PCR. Lactate secretion from primary HPMCs from women with and without endometriosis was compared in vitro. HPMCs and immortalised mesothelial cells (MeT-5a cell line) were treated with compounds that alter the activity of glycolytic enzymes i) PDK1 (dichloroacetate) and ii) LDHA (galloflavin) and their impact on glycolysis was analysed.
Results and discussion: Endometriosis lesions had higher concentrations of MCT1 mRNA (P<0.01) compared with adjacent peritoneum while expression of MCT4 was higher in the peritoneum tissue recovered adjacent to lesions (P<0.01). HPMCs from women with endometriosis showed an increased lactate secretion in vitro (P<0.05). Treatment of HPMCs with dichloroacetate and galloflavin both reduced mRNA expression of key glycolytic markers and lactate secretion. These results suggested that endometriosis is associated with a shift in the metabolic activity of mesothelial cells resulting in increased secretion of lactate (Warburg-like effect) and repurposing of anticancer drugs (dichloroacetate, galloflavin) that target lactate metabolism may offer potential as therapeutics for endometriosis.
11 Jul 2016 - 11 Jul 2016