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Published on: August 13, 2019
SR-16234, a Unique Selective Estrogen Receptor Modulator, Suppressed Proliferation and Pain-Related Factor Expression
Emiko Yamane1, Yukihiro Azuma1, Mei Matsumoto1
1Division of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Yonago, Japan.
Problem:
What is the effect of SR-16234 (SR), a selective estrogen receptor (ER) modulator, on human endometriotic stromal cells (ESCs)?
Method Of Study:
Endometriotic tissues were obtained from 21 patients undergoing laparoscopic surgery for ovarian endometriomas (OEs). Normal eutopic endometrium during the luteal phase was obtained from 18 patients without endometriosis. ESCs isolated from OEs and normal eutopic endometrial stromal cells (NESCs) were cultured with SR and subsequently exposed to tumor necrosis factor (TNF)-α. After 48 h of incubation, the effect of SR on cell proliferation was evaluated by the WST-8 assay. The gene expressions of inflammatory and pain-related factors, including interleukin (IL)-6, IL-8, cyclooxygenase (COX)-2, transient receptor potential vanilloid (TRPV)1, ESR1, and ESR2, were evaluated by real-time RT-PCR. The phosphorylation of Inhibitor κBα (IκBα), extracellular signal-regulated kinase (ERK)1/2, and Protein Kinase B (AKT) were evaluated by western blot analysis. ILs, prostaglandin (PG) E2, and intranuclear p65 syntheses were assessed by ELISA.
Results:
SR treatment repressed TNF-α-induced proliferation by 20% in ESCs but not NESCs. SR also reduced IL-6, IL-8, COX-2, TRPV1, ESR1, and ESR2 mRNA expressions and ILs protein, and PGE2 synthesis in ESCs, whereas in NESCs, only TRPV1 mRNA expression was decreased. SR suppressed TNF-α-induced phosphorylated IκBα levels by approximately 50%, and intranuclear p65 protein was reduced by 30% compared to addition of only TNF-α in ESCs. However, SR did not affect the phosphorylation of AKT and ERK1/2.
Conclusions:
SR appears to be a potential therapeutic agent for endometriosis by suppressing inflammatory and pain-related factor expressions by inhibiting the nuclear factor-kappa B pathway.
Insights
SR-16234 (SR), a selective estrogen receptor modulator, reduces inflammation and pain in human endometriotic stromal cells (ESCs). This compound inhibits key inflammatory pathways, suggesting its potential as a novel endometriosis therapy.
Area of Science:
- Endocrinology
- Reproductive Biology
- Molecular Biology
Background:
- Endometriosis is a chronic inflammatory condition characterized by endometrial tissue outside the uterus.
- Endometriotic stromal cells (ESCs) play a crucial role in disease pathogenesis, promoting inflammation and pain.
- Selective estrogen receptor (ER) modulators are being investigated for therapeutic potential in hormone-dependent diseases.
Purpose of the Study:
- To investigate the effect of SR-16234 (SR), a novel ER modulator, on human ESCs.
- To evaluate SR's impact on TNF-α-induced proliferation and inflammatory mediator expression in ESCs.
- To elucidate the molecular mechanisms underlying SR's action in ESCs.
Main Methods:
- Human ESCs and normal eutopic endometrial stromal cells (NESCs) were isolated and cultured.
- Cells were treated with SR-16234 and subsequently exposed to tumor necrosis factor-α (TNF-α).
- Cell proliferation, gene expression (IL-6, IL-8, COX-2, TRPV1, ESR1, ESR2), protein phosphorylation (IκBα, ERK1/2, AKT), and inflammatory markers (ILs, PGE2, p65) were assessed.
Main Results:
- SR-16234 significantly repressed TNF-α-induced proliferation in ESCs but not NESCs.
- SR treatment reduced mRNA expression of inflammatory and pain-related factors (IL-6, IL-8, COX-2, TRPV1, ESR1, ESR2) and protein levels of ILs and PGE2 in ESCs.
- SR suppressed TNF-α-induced IκBα phosphorylation and intranuclear p65 levels, indicating inhibition of the NF-κB pathway, without affecting AKT or ERK1/2 phosphorylation.
Conclusions:
- SR-16234 demonstrates therapeutic potential for endometriosis by mitigating inflammation and pain.
- The mechanism involves the suppression of inflammatory and pain-related factors via inhibition of the nuclear factor-kappa B (NF-κB) pathway.
- SR-16234 warrants further investigation as a novel treatment strategy for endometriosis.
