ID2 mediates the transforming growth factor-β1-induced Warburg-like effect seen in the peritoneum of women with endometriosis

Is inhibitor of DNA-binding protein 2 (ID2) a mediator of the transforming growth factor (TGF)-beta 1-induced Warburg-like effect seen in the peritoneum of women with endometriosis? The TGF-beta 1-induced changes in the metabolic phenotype of peritoneal mesothelial cells from women with endometriosis are mediated through the ID2 pathway. TGF-beta 1 induces the metabolic conversion of glucose to lactate via aerobic glycolysis (the 'Warburg effect') in the peritoneum of women with endometriosis, through increased expression of the transcription factor hypoxia inducible factor alpha (HIF-1 alpha). ID proteins are transcriptional targets of TGF-beta 1. Expression of ID2 was investigated in luteal phase peritoneal biopsies from women with regular menstrual cycles, with and without endometriosis (n = 8-10 each group) by quantitative RT-PCR (qRT-PCR) and immunohistochemistry. ID2 mRNA expression in primary human peritoneal mesothelial cells (HPMC) and immortalized mesothelial cells (MeT-5A) was assessed by qRT-PCR (n = 6). The effects of TGF-beta 1 and ID2 siRNA on HIF-1 alpha mRNA expression and lactate secretion was assessed using qRT-PCR and a colorimetric lactate assay. ID2 is localized to peritoneal mesothelial and stromal cells of women with and without endometriosis. ID2 mRNA expression is lower in peritoneum adjacent to the endometriosis lesions compared to distal sites (P < 0.01). Exposure of HPMC and MeT-5A cells to physiological concentrations of TGF-beta 1 decreases ID2 mRNA expression (P < 0.01, P < 0.001, respectively, versus control). ID2 knockdown increases HIF-1 alpha mRNA expression (P < 0.01) and lactate secretion (P < 0.05 versus scrambled control) to the same degree as with exposure to TGF-beta 1. Primary human cell cultures and a cell line were used in this study, and thus the results may not fully represent the situation in vivo. The results should also be replicated using a larger number of samples. Novel therapeutics that target the TGF beta/ID pathway offer a potential role in the treatment of endometriosis. None. This work was funded by a Wellbeing of Women research grant (R42533) awarded to A.W.H., J.K.B. and W.C.D.; and an MRC Centre Grant G1002033. V.J.Y. received grant support from Federation of Women Graduates (134225) and a PhD studentship from the College of Medicine and Veterinary Medicine at the University of Edinburgh. There are no competing interests to declare.