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.

Dienogest enhances autophagy induction in endometriotic cells by impairing activation of AKT, ERK1/2, and mTOR

“…However, endometriotic cells have been shown to respond abnormally to ovarian steroids, which contributes to the dysregulation of autophagy in these cells (22). Consistent with this finding, our results showed that progesterone treatment did not affect the induction of autophagy in estrogen-treated ECSCs, suggesting that aberrant autophagy induction in endometriotic cells may be associated with the subnormal response to progesterone known as progesterone resistance.…”

“…The therapeutic mechanisms of progestin may include antiovulatory activity, resulting in reduced serum E levels (10), and/or direct antiproliferative and anti-inflammatory effects on endometriotic cells (39)(40)(41). However, it is still unclear whether progestin directly affects the induction of autophagy in endometriotic cells, although autophagy is known to be involved in the pathogenesis of endometriosis by affecting apoptosis (22). Therefore, to elucidate the therapeutic mechanisms of progestin, we evaluated the effects of dienogest on the induction of autophagy in endometriotic cells.…”

“…These steroids are the two central balancing factors in the human endometrium (21,22). Indeed, the induction of autophagy in endometrial cells treated with estrogen alone (the proliferative phase) increased with the addition of progesterone (the secretory phase) and with the removal of estrogen and progesterone…”

“…Indeed, autophagy is induced in human malignant glioma (44) and gastric carcinoma cells (45) upon inhibition of AKT or ERK1/2 and the subsequent decrease in mTOR activity. It is interesting that endometriotic lesions have been shown to exhibit enhanced activation of AKT, ERK1/2, and mTOR compared with the normal endometrium (22,(46)(47)(48). These findings suggest that inappropriate activation of AKT and ERK1/2 may lead to the derepression of mTOR activity and the subsequent inhibition of autophagy found in endometriotic tissue.…”

“…However, autophagy is suppressed in endometriotic cells due to derepression of mammalian target of rapamycin (mTOR), a major negative regulator of autophagy, which results in decreased endometriotic cell apoptosis (22). These findings implicate a direct role for mTORmediated suppression of autophagy in the pathogenesis of endometriosis.…”