title: Menopause-induced uterine epithelium atrophy results from arachidonic acid/prostaglandin E2 axis inhibition-mediated autophagic cell death.
abstract: Women experience menopause later in life. Menopause is characterized by dramatically decreased circulating estrogen level secondary to loss of ovarian function and atrophic state of genital organs. However, the molecular mechanisms for this process are not fully understood. In this study, we aimed to investigate the potential molecular mechanisms that underlie menopause-induced uterine endometrial atrophy. Our data showed that autophagy was activated in the uterine epithelial cells of both ovariectomized rats and peri-menopausal females. Endoplasmic reticulum (ER) stress occurred even prior to autophagy induction. Integrated bioinformatics analysis revealed that ER stress induced downstream decreased release of arachidonic acid (AA) and downregulation of AA/prostaglandin E2 (PGE2) axis, which led to Akt/mTOR signaling pathway inactivation. Consequently, autophagosomes were recruited and LC3-dependent autophagy was induced in uterine epithelial cells. Treatment with exogenous E2, PGE2, salubrinal or RNAi-mediated silencing of key autophagy genes could effectively counteract estrogen depletion-induced autophagy. Collectively, autophagy is a critical regulator of the uterine epithelium that accounts for endometrial atrophy after menopause.
authors: Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics &Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, and The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
authors: Shengtao
authors: S
authors: Zhou
authors: Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics &Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, and The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
authors: Linjie
authors: L
authors: Zhao
authors: Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics &Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, and The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
authors: Tao
authors: T
authors: Yi
authors: Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics &Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, and The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
authors: Yuquan
authors: Y
authors: Wei
authors: Department of Gynecology and Obstetrics, Key Laboratory of Obstetrics &Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, and The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
authors: Xia
authors: X
authors: Zhao
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001284:Atrophy; D001343:Autophagy; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium; D005260:Female; D006801:Humans; D008593:Menopause; D023421:Models, Animal; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000378:metabolism / Q000473:pathology*
chemical_list: D016718:Arachidonic Acid; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D015232:Dinoprostone