Dienogest regulates apoptosis, proliferation, and invasiveness of endometriotic cyst stromal cells via endoplasmic reticulum stress induction

JongYeob Choi, MinWha Jo, Eunyoung Lee, Dong-Yun Lee, Dong‐Yun Lee, DooSeok Choi
Molecular human reproduction · 2019 · vol. 26(1) , pp. 30–39 · doi:10.1093/molehr/gaz064 · PMID:31814016 · W2996400686
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Dienogest treatment increases endoplasmic reticulum stress and apoptosis while decreasing proliferation and invasiveness in endometriotic stromal cells by upregulating CHOP expression through PERK and IRE1 signaling.

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Abstract

Dienogest, a specific progesterone receptor agonist, is used in the treatment of endometriosis. However, it is still unclear as to the mechanisms of therapeutic effects on endometriosis. Our recent study showed that endometriosis may be the result of aberrant endoplasmic reticulum (ER) stress induction due to progesterone resistance. This finding suggests that the regulation of ER stress induction may play a key role in treatment of endometriosis. Therefore, the anti-endometriotic effects of dienogest may be mediated by regulation of ER stress. To test this hypothesis, we elucidate whether dienogest affects endometriotic stromal cell apoptosis, proliferation and invasiveness by modulating ER stress-induced CCAAT/enhancer-binding protein homologous protein (CHOP) expression. Specifically, PRKR-like ER kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4), inositol-requiring kinase 1 (IRE1)/TNF receptor-associated factor 2 (TRAF2)/apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) signaling, and downstream CHOP were evaluated to determine the involved ER stress-mediated regulation mechanism of CHOP expression. Our results show that progesterone treatment did not have any significant effects on ER stress, apoptosis, proliferation, and invasion in estrogen-treated endometriotic cyst stromal cells (ECSCs). However, dienogest treatment upregulated the induction of ER stress. It also led to increased apoptosis, and decreased proliferation and invasiveness. These dienogest-induced changes in apoptosis, proliferation and invasiveness were reversed by the ER stress inhibitor salubrinal. Furthermore, dienogest-induced ER stress increased CHOP expression through activation of both PERK/elf2α/ATF4 and IRE1/TRAF2/ASK1/JNK signaling. This upregulation was blocked by transfection with PERK and IRE1 siRNA, which decreased apoptosis and increased the proliferation and invasiveness of dienogest-treated ECSCs. Taken together, our findings indicate that dienogest enhances ER stress induction in endometriotic stromal cells, which affects apoptosis, proliferation and invasiveness via CHOP upregulation.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Cysts eIF-2 Kinase Endometriosis Endoplasmic Reticulum Stress Hormone Antagonists Nandrolone Transcription Factor CHOP Activating Transcription Factor 4 Activating Transcription Factor 4 Activating Transcription Factor 4 Adult Apoptosis Apoptosis Cell Movement Cell Movement Cell Proliferation Cell Proliferation Cysts Cysts Cysts

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