Effects of hypoxia-induced pyruvate dehydrogenase kinase-1 and neurotrophic receptor tyrosine kinase-2 in the pathogenesis of endometriosis

Abstract

Endometriosis is a common gynecological disease which affects about 10% of women in reproductive-age It causes chronic pelvic pain dysmenorrhea and infertility and decreases the life quality of patients However the cause of endometriosis is complex and largely unclear Our previous study demonstrates that HIF-1? is up-regulated in ectopic endometriotic stromal cells Since hypoxia is a critical factor leading to many pathological processes thus the overall objective of this study is to investigate hypoxia-induced pathological alteration that may contribute to the progression of endometriosis and to further explore the potential hormone-independent treatments base on the hypoxia-induced pathological alteration Here we found the expression of pyruvate dehydrogenase kinase 1 (PDK1) a critical enzyme in regulating glucose metabolism was increased in ectopic stromal cell Molecular characterization reveals that overexpression of PDK1 is induced by hypoxia through transcriptional regulation Upregulation of PDK1 in ectopic endometriotic stromal cells is accompanied by increases in lactate production and oxygen consumption rate as compared to eutopic endometrial stromal cells Furthermore our data show that lactate production and oxygen consumption rate of ectopic stromal cells were decreased when cells were treated with PDK1 inhibitor dichloroacetate In addition hypoxia-induced PDK1 expression prevents cells from H2O2- and low nutrient-induced cell death On the other hand we performed the bioinformatics analysis and found neurotrophic receptor tyrosine kinase 2 (NTRK2 also known as TrkB) as a potential candidate for treatment Both in clinical specimen and the endometriosis mouse model the levels of NTRK2 were markedly upregulated in the lesions In addition we found that hypoxia can induce NTRK2 expression in a HIF1?-dependent manner Administration of ANA-12 a selective non-competitive antagonist of NTRK2 significantly induced endometriotic stromal cells death suggesting it may be a potential therapeutic agent Indeed treatment of endometriotic lesion-bearing mice with ANA-12 (1 5 mg/kg body weight) caused the ectopic lesions regression Taken together our results demonstrate that hypoxia-induced pathological alterations involve in the progression of endometriosis which can be the target of treatment for endometriosis

Date of Award	2019
Original language	English
Supervisor	Shaw-Jenq Tsai (Supervisor)