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Farnesoid X Receptor Agonist GW4064 Inhibits Aromatase and ERβ Expression in Human Endometriotic Stromal Cells
- Source :
- Reproductive sciences (Thousand Oaks, Calif.). 26(8)
- Publication Year :
- 2018
-
Abstract
- Endometriosis is an estrogen-dependent disease. Farnesoid X receptor (FXR) activation has been shown to inhibit estrogen signaling in breast cancer and testicular tumors. However, the role of FXR in endometriosis is still poorly understood. Here, we aimed to investigate whether FXR activation by its synthetic agonist GW4064 has a therapeutic effect on endometriosis and the underlying molecular mechanisms. We found that the expression of FXR (encoded by the NR1H4 gene) in endometriotic tissues and stromal cells (ESCs) was higher than that in eutopic endometrial tissues and stromal cells. The GW4064 treatment led to a dose-dependent decrease in aromatase and estrogen receptor β (ERβ) expression and induced ERK1/2, p38, AMPK, and Stat3 activation in ESCs. In contrast, ERK1/2 inhibitor reversed the GW4064-induced reduction in aromatase expression. In addition, treatment with p38, AMPK, and Stat3 inhibitors or small interfering RNAs could also reverse the GW4064-induced reduction of ERβ expression in ESCs. The GW4064 treatment markedly increased Stat3 phosphorylation, enhancing the binding of Stat3 to the ESR2 promoter, which resulted in the downregulation of ERβ. Coimmunoprecipitation assay and chromatin immunoprecipitation analysis revealed that FXR was able to compete with cyclic AMP response element-binding (CREB) protein for binding to a common sequence on the aromatase promoter region after GW4064 treatment in ESCs. Moreover, treatment of endometriosis xenografts with GW4064 suppressed aromatase and ERβ expression in nude mice. Our results suggest that FXR may represent a potential therapeutic target for future therapy.
- Subjects :
- 0301 basic medicine
Agonist
STAT3 Transcription Factor
Stromal cell
medicine.drug_class
Estrogen receptor
Mice, Nude
Receptors, Cytoplasmic and Nuclear
p38 Mitogen-Activated Protein Kinases
03 medical and health sciences
Endometrium
Mice
0302 clinical medicine
Aromatase
Downregulation and upregulation
medicine
Animals
Estrogen Receptor beta
Humans
Cyclic AMP Response Element-Binding Protein
030219 obstetrics & reproductive medicine
biology
Chemistry
Adenylate Kinase
Obstetrics and Gynecology
AMPK
Isoxazoles
030104 developmental biology
biology.protein
Cancer research
Farnesoid X receptor
Female
Stromal Cells
Chromatin immunoprecipitation
Signal Transduction
Subjects
Details
- ISSN :
- 19337205
- Volume :
- 26
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Reproductive sciences (Thousand Oaks, Calif.)
- Accession number :
- edsair.doi.dedup.....cf19cf4d9161cd8302b6a38ed6289521