Transforming Growth Factor-β Induced Warburg-Like Metabolic Reprogramming May Underpin the Development of Peritoneal Endometriosis

• Published in: The journal of clinical endocrinology and metabolism 2014-09, Vol.99 (9), p.3450-3459
• Main Authors: Young, Vicky J, Brown, Jeremy K, Maybin, Jacqueline, Saunders, Philippa T. K, Duncan, W. Colin, Horne, Andrew W
• Format: Article
• Language: English
• Subjects: Ascitic Fluid - metabolism; Cell Line, Transformed; Endocrine Research; Endometriosis - genetics; Endometriosis - metabolism; Endometriosis - pathology; Endometrium - metabolism; Endometrium - pathology; Epithelial Cells - cytology; Epithelial Cells - metabolism; Female; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Glycolysis - genetics; Glycolysis - physiology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Isoenzymes - genetics; Isoenzymes - metabolism; L-Lactate Dehydrogenase - genetics; L-Lactate Dehydrogenase - metabolism; Lactate Dehydrogenase 5; Lactic Acid - metabolism; Oxidative Phosphorylation; Peritoneum - cytology; Peritoneum - metabolism; Peritoneum - pathology; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; RNA, Messenger - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2014-1026

Context: TGF-β is believed to play a major role in the etiology of peritoneal endometriosis. In tumors, TGF-β induces the metabolic conversion of glucose to lactate via glycolysis, a process referred to as the “Warburg effect.” Lactate increases cell invasion, angiogenesis, and immune suppression, all crucial steps in the development of endometriosis. Objective: The aim of this study was to determine whether TGF-β induces a “Warburg-like” effect in peritoneal endometriosis. Design: The study was informed by human tissue analysis and cel culture. Setting: The study was conducted at the university research institute. Patients or Other Participants: We studied women undergoing surgical investigation for endometriosis. Interventions: Concentrations of lactate and TGF-β1 in peritoneal fluid (n = 16) were measured by commercial assay. Expression of genes implicated in glycolysis was measured in endometrial and peritoneal biopsies (n = 31) by quantitative RT-PCR and immunohistochemistry. The effect of TGF-β1 on primary human peritoneal mesothelial cells (n = 6) and immortalized mesothelial (MeT-5A) cells (n = 3) was assessed by quantitative RT-PCR, Western blot, and commercial assays. Main Outcome Measures: Lactate, TGF-β1, and markers of glycolysis were measured. Results: Concentrations of lactate in peritoneal fluid paralleled those of TGF-β1, being significantly higher in women with endometriosis compared to women without (P < .05). Endometriosis lesions expressed higher levels of glycolysis-associated genes HIF1A, PDK1, and LDHA than eutopic endometrium, and adjacent peritoneum had higher levels of HIF1A and SLC2A1 than peritoneum from women without disease (P < .05 to P < .001). Exposure of mesothelial cells to TGF-β1 increased production of lactate (P < .05), increased HIF1A mRNA (P < .05), and protein, and increased concentrations of mRNAs encoded by glycolysis-associated genes (LDHA, PDK1, SLC2A1; P < .05). Conclusions: A change in the metabolic phenotype of endometriosis lesions and peritoneal mesothelium in women with endometriosis may favor development of endometriosis.