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

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, a...

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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
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Summary: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.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2014-1026