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.
Highlights
Endometriosis (EMS) is a common inflammatory gynecological disease characterized by the presence of endometrial-like lesions located outside the uterus, causing chronic pelvic pain and infertility [1], and affects approximately 5–10% of women during their reproductive ages [2]
We found that there was no difference in mRNA levels of estrogen receptor b (ERb), nuclear respiratory factor-1 (NRF1), and matrix metalloproteinase-1 (MMP1) in EM cells, but levels were 1.45 and 1.43 times higher, respectively, in Human Endometrial Epithelial Cells (HEEC) cells
Our results showed that BAinduced relative reporter activities were around 60% compared to the control group for the deletion constructs of -2000, -1600, -1200, -800, -400, and -300, while the reporter activities reached around 100% for the deletion constructs of -200, -100, and -0, indicating that BAinduced reporter activity suppression was restored in the deletion constructs of -200, -100, and -0, and the betulinic acid (BA)-responsive transcriptional element is located in the range of -300~0 on the ERb promoter
Summary
Endometriosis (EMS) is a common inflammatory gynecological disease characterized by the presence of endometrial-like lesions located outside the uterus, causing chronic pelvic pain and infertility [1], and affects approximately 5–10% of women during their reproductive ages [2]. It has been reported that ERb plays an important role in EMS pathogenesis by modulating its target genes [6], including NRF1, SOD2, COX2, and MMP1, and specific ERb suppression, such as ERb antagonist [17], has been used for treatment of endometriosis, but with many of limitations and side effects. In this case, development of a nontoxic and specific ERb suppression agent for treatment of endometriosis is still quite necessary
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