Farnesoid X Receptor Agonist GW4064 Inhibits Aromatase and ERβ Expression in Human Endometriotic Stromal Cells

Wu PL, Pei-Li Wu, Peili Wu, Cheng Zeng, Zhou YF, Ying-Fang Zhou, Yingfang Zhou, Ling Yin, Yin L, Yu XL, Xiaolan Yu, Xiao-Lan Yu, Qing Xue, Xue Q
Reproductive sciences (Thousand Oaks, Calif.) · 2018 · vol. 26(8) , pp. 1111–1120 · doi:10.1177/1933719118808912 · PMID:30428773 · W2901898290
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The farnesoid X receptor agonist GW4064 was found to inhibit aromatase and ERβ expression in human endometriotic stromal cells.

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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.

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MeSH descriptors

Aromatase Endometrium Estrogen Receptor beta Isoxazoles Receptors, Cytoplasmic and Nuclear Stromal Cells Adenylate Kinase Adenylate Kinase Animals Aromatase Cyclic AMP Response Element-Binding Protein Cyclic AMP Response Element-Binding Protein Endometrium Endometrium Estrogen Receptor beta Female Humans Isoxazoles Mice Mice, Nude

Funding

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[{'doi': '10.13039/501100001809', 'name': 'National Natural Science Foundation of China', 'awards': ['81671427']}]

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