Infertility Clinic, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea.
Mol Hum Reprod. 2014 Apr;20(4):309-17. doi: 10.1093/molehr/gat091. Epub 2013 Dec 6.
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.
哺乳动物雷帕霉素靶蛋白（mTOR）是已知的自噬的主要负调节因子。最近的研究表明，mTOR 活性在子宫内膜异位症病变中异常增加。在子宫内膜异位症中，异常的 mTOR 活性可能导致子宫内膜细胞自噬的改变，这可能影响细胞凋亡，因为子宫内膜细胞自噬直接参与凋亡的调节。为了验证这一假设，我们研究了异常的 mTOR 活性是否改变了子宫内膜细胞的自噬，并与卵巢子宫内膜异位囊肿中的细胞凋亡有关。我们的结果表明，在正常子宫内膜中，随着月经周期的进展，mTOR 抑制可诱导子宫内膜细胞自噬增加，并且与细胞凋亡相关。然而，在卵巢子宫内膜异位囊肿的异位组织中，自噬、mTOR 活性和凋亡在整个月经周期中保持不变，这表明在月经周期中，通过抑制 mTOR 活性，异位组织中保持恒定的自噬水平，并与细胞凋亡减少有关。事实上，与正常子宫内膜相比，在异位组织的分泌期，增加的 mTOR 活性抑制了自噬和细胞凋亡诱导。此外，为了确定 mTOR 介导的自噬诱导对子宫内膜异位细胞凋亡的直接影响，用雷帕霉素（mTOR 抑制剂）和 3-甲基腺嘌呤（3-MA，自噬抑制剂）处理子宫内膜异位细胞。尽管雷帕霉素处理诱导了自噬，并导致细胞凋亡促进，但加入 3-MA 可逆转促凋亡作用，表明 mTOR 抑制通过诱导自噬促进子宫内膜异位细胞凋亡。总之，我们的结果表明，卵巢子宫内膜异位囊肿中的异常 mTOR 活性导致子宫内膜细胞自噬的改变，这与异常的细胞凋亡有关。
