The Role of Autophagy in Human Endometrium1

Abstract

Autophagy appears to play an important role in the normal development and maintenance of homeostasis in a variety of tissues, including the female reproductive tract. However, the role of autophagy and the association between autophagy and apoptosis in cyclic remodeling of the human endometrium have not been described. Therefore, we investigated the involvement of autophagy during the human endometrial cycle and its association with apoptosis. Endometrial samples were obtained from 15 premenopausal, nonpregnant women who underwent hysterectomies for benign gynecological reasons. The autophagy-associated protein, microtubule-associated protein 1 light chain 3 alpha (MAP1LC3A), was immunolocalized, and its expression level was measured by Western blot analysis. Apoptosis was evaluated by measuring the expression level of cleaved caspase 3 protein. MAP1LC3A protein was primarily expressed within the endometrial glandular cells and increased during the secretory phase. The expression level of the membrane-bound form of MAP1LC3A (MAP1LC3A-II) also increased as the menstrual cycle progressed, reaching a maximum level during the late secretory phase. This pattern coincided with the expression of cleaved caspase 3. Furthermore, expression of MAP1LC3A-II and cleaved caspase 3 increased in the in vitro-cultured endometrial cancer cells when estrogen and/or progesterone were withdrawn from the culture media to mimic physiological hormonal changes. These findings suggest that endometrial cell autophagy is directly involved in the cyclic remodeling of the human endometrium and is correlated with apoptosis. In addition, we inhibited autophagic processes using 3-methyladenine (3-MA) or bafilomycin A1 (Baf A1) to evaluate the role of autophagy in apoptosis induction in endometrial cancer cells. While the inhibition of autophagosome formation using 3-MA did not decrease apoptosis or cell death, the inhibition of autophagosome degradation by fusion with lysosomes using Baf A1 increased apoptosis and cell death, suggesting that the accumulation of autophagosomes induces apoptosis. Furthermore, Baf A1-induced apoptotic cell death was decreased by the apoptosis inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK). In conclusion, these results indicate that autophagy is involved in the endometrial cell cycle affecting apoptosis and is most prominent during the late secretory phase.

IL15 promotes growth and invasion of endometrial stromal cells and inhibits killing activity of NK cells in endometriosis

“…It has been reported that the induction of autophagy exerts a proapoptotic effect on normal human endometrial cells (Choi et al 2012). Compared with normal endometria, a remarkable activation of the autophagic process was observed in ectopic endometrial lesions (Nasu et al 2011).…”

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

“…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…”

“…We recently showed that the induction of autophagy exerts a proapoptotic effect on normal human endometrial cells (21). 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).…”

Suppression of autophagic activation in the mouse uterus by estrogen and progesterone

“…In human endometrial cells, autophagy seems to be involved in the cell cycle (Choi et al 2012). However, whether ovarian steroid hormones regulate autophagic response in the mouse uterus has not been established.…”