title: Differential induction of autophagy by mTOR is associated with abnormal apoptosis in ovarian endometriotic cysts.
abstract: Mammalian target of rapamycin (mTOR) is known to be a major negative regulator of autophagy. Recent studies have shown that mTOR activity is abnormally increased in endometriotic lesions. In endometriosis, abnormal mTOR activity may contribute to the alteration of endometrial cell autophagy, which may affect apoptosis because endometrial cell autophagy is directly involved in the regulation of apoptosis. To test this hypothesis, we investigated whether endometrial cell autophagy is altered by aberrant mTOR activity and is associated with apoptosis in ovarian endometriotic cysts. Our results show that endometrial cell autophagy induction was increased by mTOR inhibition as the menstrual cycle progresses in the normal endometrium, and that it is correlated with apoptosis. However, in endometriotic tissues from ovarian endometriotic cysts, autophagy, mTOR activity and apoptosis were constant throughout the menstrual cycle, suggesting that a constant level of autophagy is maintained by disinhibition of mTOR activity during the menstrual cycle in endometriotic tissues and is related to decreased apoptosis. Indeed, compared with normal endometrium, increased mTOR activity during the secretory phase in endometriotic tissues inhibited autophagy and apoptosis induction. In addition, to determine the direct effect of autophagy induction mediated by mTOR on endometriotic cell apoptosis, endometriotic cells were treated with rapamacin (mTOR inhibitor) with and without 3-methyladenine (3-MA, autophagy inhibitor). Although rapamycin treatment induced autophagy and led to apoptosis promotion, the pro-apoptotic effect of rapamycin was reversed by the addition of 3-MA, suggesting that mTOR inhibition promotes endometriotic cell apoptosis via autophagy induction. In conclusion, our results suggest that aberrant mTOR activity in ovarian endometriotic cysts leads to alteration of endometrial cell autophagy, which is associated with abnormal apoptosis.
authors: Infertility Clinic, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea.
authors: JongYeob
authors: J
authors: Choi
authors: MinWha
authors: M
authors: Jo
authors: EunYoung
authors: E
authors: Lee
authors: Hyo Jeong
authors: HJ
authors: Kim
authors: DooSeok
authors: D
authors: Choi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics*; D003560:Cysts / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008597:Menstrual Cycle / Q000502:physiology; D061251:Primary Cell Culture; D020123:Sirolimus / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C025946:3-methyladenine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000225:Adenine; D020123:Sirolimus
keywords: apoptosis; autophagy; endometriosis; mTOR