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

Abstract

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.

Water-Extracted Prunella vulgaris Alleviates Endometriosis by Reducing Aerobic Glycolysis

“…The estrogen-related receptors (ERRs) are another possible factor for controlling pyruvate metabolism, resulting in the stimulated transcription of PDK2 and PDK4 ( Zhang et al, 2006 ; Jeong et al, 2012 ). Several studies have suggested that P. vulgaris possesses estrogen resistant properties ( Huang et al, 2006 ; Collins et al, 2009 ; Kim et al, 2014 ; Xiang et al, 2020 ). However, in our study, we observed that PV regulates the expression of PDK1/3 and activity of LDHA beside of anti-estrogenic effect.…”

“…The expression of enzymes related to glucose metabolism, such as enolase 1 and M2-type pyruvate kinase, can be decreased with P. vulgaris treatment ( Wang et al, 2014 ). Several studies have demonstrated that P. vulgaris and betulinic acid, one of its active ingredients, have an inhibitory effect on the growth of endometrial cells through anti-estrogenic activity ( Huang et al, 2006 ; Collins et al, 2009 ; Xiang et al, 2020 ). However, the molecular mechanisms underlying the inhibition of endometriosis by P. vulgaris have not been fully elucidated.…”

A proposed novel genetic and epigenetic effects of Betulinic acid against breast cancer cells: in silico and in vitro study.

“…The effect of BA on epigenetic gene expression was rarely investigated, a single study reported that BA treatment caused a suppression in ERβ expression through epigenetic modi cation of its promoter in endometriotic cells (41). To investigate if alteration of cellular epigenetics might contribute to the antitumor activity of BA, we examined the methylation status of the promoter region of two target genes in the Kaiso signaling pathway, a known oncogene; c-Myc, and a tumor suppressor gene; CDKN2A.…”

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

“…Endometriosis is a gynecological inflammatory disease that affects between 5% and 10% of women during the reproductive phase; in endometriosis, an increase in the overexpression of estrogen receptor β (ER-β) compared with estrogen receptor α (ER-α) has been reported, which promotes endometriotic cell proliferation and inflammation. BA was found to suppress ER-β expression by targeting ER-β promoter genes that further induced apoptosis in endometriotic cells and decreased the production of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α [ 95 ].…”