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Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway

Endometriosis is an inflammatory gynecological disorder characterized by endometrial tissue growth located outside of the uterine cavity in addition to chronic pelvic pain and infertility. In this study, we aim to develop a potential therapeutic treatment based on the pathogenesis and mechanism of E...

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Autores principales: Xiang, Dongfang, Zhao, Min, Cai, Xiaofan, Wang, Yongxia, Zhang, Lei, Yao, Helen, Liu, Min, Yang, Huan, Xu, Mingtao, Li, Huilin, Peng, Huijuan, Wang, Min, Liang, Xuefang, Li, Ling, Yao, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759155/
https://www.ncbi.nlm.nih.gov/pubmed/33362719
http://dx.doi.org/10.3389/fendo.2020.604648
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author Xiang, Dongfang
Zhao, Min
Cai, Xiaofan
Wang, Yongxia
Zhang, Lei
Yao, Helen
Liu, Min
Yang, Huan
Xu, Mingtao
Li, Huilin
Peng, Huijuan
Wang, Min
Liang, Xuefang
Li, Ling
Yao, Paul
author_facet Xiang, Dongfang
Zhao, Min
Cai, Xiaofan
Wang, Yongxia
Zhang, Lei
Yao, Helen
Liu, Min
Yang, Huan
Xu, Mingtao
Li, Huilin
Peng, Huijuan
Wang, Min
Liang, Xuefang
Li, Ling
Yao, Paul
author_sort Xiang, Dongfang
collection PubMed
description Endometriosis is an inflammatory gynecological disorder characterized by endometrial tissue growth located outside of the uterine cavity in addition to chronic pelvic pain and infertility. In this study, we aim to develop a potential therapeutic treatment based on the pathogenesis and mechanism of Endometriosis. Our preliminary data showed that the expression of estrogen receptor β (ERβ) was significantly increased, while ERα was significantly decreased, in endometriotic cells compared to normal endometrial cells. Further investigation showed that betulinic acid (BA) treatment suppressed ERβ expression through epigenetic modification on the ERβ promoter, while had no effect on ERα expression. In addition, BA treatment suppresses ERβ target genes, including superoxide dismutase 2 (SOD2), nuclear respiratory factor-1 (NRF1), cyclooxygenase 2 (COX2), and matrix metalloproteinase-1 (MMP1), subsequently increasing oxidative stress, triggering mitochondrial dysfunction, decreasing elevated proinflammatory cytokines, and eventually suppressing endometriotic cell proliferation, mimicking the effect of ERβ knockdown. On the other hand, gain of ERβ by lentivirus infection in normal endometrial cells resulted in increased cell proliferation and proinflammatory cytokine release, while BA treatment diminished this effect through ERβ suppression with subsequent oxidative stress and apoptosis. Our results indicate that ERβ may be a major driving force for the development of endometriosis, while BA inhibits Endometriosis through specific suppression of the ERβ signaling pathway. This study provides a novel therapeutic strategy for endometriosis treatment through BA-mediated ERβ suppression.
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spelling pubmed-77591552020-12-25 Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway Xiang, Dongfang Zhao, Min Cai, Xiaofan Wang, Yongxia Zhang, Lei Yao, Helen Liu, Min Yang, Huan Xu, Mingtao Li, Huilin Peng, Huijuan Wang, Min Liang, Xuefang Li, Ling Yao, Paul Front Endocrinol (Lausanne) Endocrinology Endometriosis is an inflammatory gynecological disorder characterized by endometrial tissue growth located outside of the uterine cavity in addition to chronic pelvic pain and infertility. In this study, we aim to develop a potential therapeutic treatment based on the pathogenesis and mechanism of Endometriosis. Our preliminary data showed that the expression of estrogen receptor β (ERβ) was significantly increased, while ERα was significantly decreased, in endometriotic cells compared to normal endometrial cells. Further investigation showed that betulinic acid (BA) treatment suppressed ERβ expression through epigenetic modification on the ERβ promoter, while had no effect on ERα expression. In addition, BA treatment suppresses ERβ target genes, including superoxide dismutase 2 (SOD2), nuclear respiratory factor-1 (NRF1), cyclooxygenase 2 (COX2), and matrix metalloproteinase-1 (MMP1), subsequently increasing oxidative stress, triggering mitochondrial dysfunction, decreasing elevated proinflammatory cytokines, and eventually suppressing endometriotic cell proliferation, mimicking the effect of ERβ knockdown. On the other hand, gain of ERβ by lentivirus infection in normal endometrial cells resulted in increased cell proliferation and proinflammatory cytokine release, while BA treatment diminished this effect through ERβ suppression with subsequent oxidative stress and apoptosis. Our results indicate that ERβ may be a major driving force for the development of endometriosis, while BA inhibits Endometriosis through specific suppression of the ERβ signaling pathway. This study provides a novel therapeutic strategy for endometriosis treatment through BA-mediated ERβ suppression. Frontiers Media S.A. 2020-12-10 /pmc/articles/PMC7759155/ /pubmed/33362719 http://dx.doi.org/10.3389/fendo.2020.604648 Text en Copyright © 2020 Xiang, Zhao, Cai, Wang, Zhang, Yao, Liu, Yang, Xu, Li, Peng, Wang, Liang, Li and Yao http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Xiang, Dongfang
Zhao, Min
Cai, Xiaofan
Wang, Yongxia
Zhang, Lei
Yao, Helen
Liu, Min
Yang, Huan
Xu, Mingtao
Li, Huilin
Peng, Huijuan
Wang, Min
Liang, Xuefang
Li, Ling
Yao, Paul
Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway
title Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway
title_full Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway
title_fullStr Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway
title_full_unstemmed Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway
title_short Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway
title_sort betulinic acid inhibits endometriosis through suppression of estrogen receptor β signaling pathway
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759155/
https://www.ncbi.nlm.nih.gov/pubmed/33362719
http://dx.doi.org/10.3389/fendo.2020.604648
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