Ovarian steroid dependence of endoplasmic reticulum stress involvement in endometrial cell apoptosis during the human endometrial cycle

Abstract

Endoplasmic reticulum (ER) stress is a common cellular stress response that enhances apoptosis to trigger cell death. However, recent studies have shown that estrogen suppresses apoptosis by inhibiting ER stress in some cell types, suggesting that ER stress-induced apoptosis is regulated by ovarian steroid hormones. In endometrial cells, ER stress may also be controlled by ovarian steroid hormones and could be involved in apoptosis induction during the menstrual cycle. To test this hypothesis, we elucidate whether ER stress is regulated by ovarian steroid hormones in human endometrial cells and if it is involved in apoptosis induction. Specifically, we sought to determine the effects of estrogen and progesterone on the PERK/eIF2α/ATF4/CHOP pathway, a pro-apoptotic pathway mediated by ER stress. Our results show that ER stress maker GRP78 expression was increased in human endometrial Ishikawa and endometrial stromal cells (ESCs) treated with tunicamycin. Addition of estrogen decreased tunicamycin-induced GRP78 expression. In contrast, progesterone treatment increased GRP78 in estrogen-treated Ishikawa and ESCs, which significantly increased CHOP expression through phosphorylation of eIF2α and upregulation of ATF4. This upregulation was accompanied by an increased apoptosis induction. The progesterone-induced increase in apoptosis was reversed by either mifepristone (progesterone receptor modulator) or salubrinal (ER stress inhibitor). Furthermore, our results also showed that GRP78, CHOP expression and apoptosis were significantly increased in endometrial cells during the secretory phase as well as by treatment with progesterone. In conclusion, our results suggest that estrogen inhibits ER stress in human endometrial cells. This inhibition is reversed by progesterone during the secretory phase, and this is directly involved in apoptosis induction.

Medroxyprogesterone acetate causes the alterations of endoplasmic reticulum related mRNAs and lncRNAs in endometrial cancer cells

“…It has been reported that ER stress by realgar quantum dots induces increased expression of CHOP, and further leads to EC cell apoptosis and necrosis [28]. Additionally, previous study has demonstrated that progesterone-induced ER stress may enhance EC apoptosis through overexpression of CHOP [25]. Our microarray data showed that HERPUD1 is also significantly increased with the fold change of 11.94.…”

“…At the beginning of ER stress, cells activate the unfolded protein response (UPR) which is mainly regulated by three ER-located sensors, including PKR-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6). Theses sensors initiate translational attenuation to inhibit further accumulation of misfolded proteins and to increase folding machinery, and facilitate ER-associated degradation to eliminate misfolded proteins in the ER [25]. If UPR is insufficient to alleviate the stress, it then leads to cell death [24].…”

Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review

“…Increased levels of E 2 reduce progesterone and inhibit endoplasmic reticulum stress in endometrial cells 157 . Increased expression of estrogen receptor (ER) isoforms has been observed in endometriotic lesions, 158,159 suggesting their contribution in regulating proliferation of the lesions.…”

Progestin Resistance and Corresponding Management of Abnormal Endometrial Hyperplasia and Endometrial Carcinoma

“…Another mechanism of progestin-induced apoptosis is the promotion of endoplasmic reticulum stress [ 23 ]. MPA may increase the expression of endoplasmic reticulum stress-related molecule HERPUD1 in Ishikawa cells by activating endoplasmic reticulum stress via the progestin-PRB pathway, then inducing cell apoptosis [ 24 ].…”