PMID- 31814016 OWN - NLM STAT- MEDLINE DCOM- 20210127 LR - 20211204 IS - 1460-2407 (Electronic) IS - 1360-9947 (Linking) VI - 26 IP - 1 DP - 2020 Jan 1 TI - Dienogest regulates apoptosis, proliferation, and invasiveness of endometriotic cyst stromal cells via endoplasmic reticulum stress induction. PG - 30-39 LID - 10.1093/molehr/gaz064 [doi] AB - 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 2alpha (eIF2alpha)/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/elf2alpha/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. CI - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com. FAU - Choi, JongYeob AU - Choi J AD - Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 06351, Korea. FAU - Jo, MinWha AU - Jo M AD - Center for Clinical Research, Samsung Biomedical Research Institute, 50 Irwon-dong, Gangnam-gu, Seoul 06351, Korea. FAU - Lee, EunYoung AU - Lee E AD - Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 06351, Korea. FAU - Lee, Dong-Yun AU - Lee DY AD - Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 06351, Korea. FAU - Choi, DooSeok AU - Choi D AD - Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 06351, Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Mol Hum Reprod JT - Molecular human reproduction JID - 9513710 RN - 0 (ATF4 protein, human) RN - 0 (DDIT3 protein, human) RN - 0 (Hormone Antagonists) RN - 0 (RNA, Small Interfering) RN - 0 (TNF Receptor-Associated Factor 2) RN - 145891-90-3 (Activating Transcription Factor 4) RN - 147336-12-7 (Transcription Factor CHOP) RN - 46M3EV8HHE (dienogest) RN - 4G7DS2Q64Y (Progesterone) RN - 6PG9VR430D (Nandrolone) RN - EC 2.7.11.1 (EIF2AK3 protein, human) RN - EC 2.7.11.1 (ERN1 protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (eIF-2 Kinase) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinase 5) RN - EC 2.7.11.25 (MAP3K5 protein, human) RN - EC 3.1.- (Endoribonucleases) SB - IM MH - Activating Transcription Factor 4/genetics/metabolism MH - Adult MH - Apoptosis/drug effects MH - Cell Movement/drug effects MH - Cell Proliferation/drug effects MH - Cysts/*drug therapy/genetics/metabolism/pathology MH - Endometriosis/*drug therapy/genetics/metabolism/pathology MH - Endometrium/drug effects/metabolism/pathology MH - Endoplasmic Reticulum/drug effects/genetics/metabolism MH - Endoplasmic Reticulum Stress/*drug effects MH - Endoribonucleases/antagonists & inhibitors/genetics/metabolism MH - Female MH - Gene Expression Regulation MH - Hormone Antagonists/*pharmacology MH - Humans MH - MAP Kinase Kinase Kinase 5/genetics/metabolism MH - MAP Kinase Signaling System MH - Nandrolone/*analogs & derivatives/pharmacology MH - Progesterone/pharmacology MH - Protein Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism MH - RNA, Small Interfering/genetics/metabolism MH - Stromal Cells/drug effects/metabolism/pathology MH - TNF Receptor-Associated Factor 2/genetics/metabolism MH - Transcription Factor CHOP/agonists/*genetics/metabolism MH - eIF-2 Kinase/antagonists & inhibitors/*genetics/metabolism OTO - NOTNLM OT - CHOP OT - ER stress OT - apoptosis OT - dienogest OT - endometriosis OT - invasiveness OT - proliferation EDAT- 2019/12/10 06:00 MHDA- 2021/01/28 06:00 CRDT- 2019/12/10 06:00 PHST- 2019/07/12 00:00 [received] PHST- 2019/10/25 00:00 [revised] PHST- 2019/12/10 06:00 [pubmed] PHST- 2021/01/28 06:00 [medline] PHST- 2019/12/10 06:00 [entrez] AID - 5645447 [pii] AID - 10.1093/molehr/gaz064 [doi] PST - ppublish SO - Mol Hum Reprod. 2020 Jan 1;26(1):30-39. doi: 10.1093/molehr/gaz064.