C-Jun NH2-Terminal Kinase and p38 Inhibition Suppresses Prostaglandin E2-Stimulated Aromatase and Estrogen Receptor Levels in Human Endometriosis

Cheng Zeng, Jianing Xu, Jia-Ning Xu, Yan Zhou, Hui-xia Yang, Huixia Yang, Yingfang Zhou, Ying-Fang Zhou, Qing Xue
The Journal of clinical endocrinology and metabolism · 2015 · vol. 100(11) , pp. E1404–E1414 · doi:10.1210/jc.2015-2031 · PMID:26394174 · W2105980677
article OA: bronze CC0 ⤵ 7 in-corpus citations
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PGE2 upregulates aromatase and ERβ in endometriosis via p38 and JNK signaling, and inhibiting these kinases reduces estradiol production and xenograft growth.

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Abstract

CONTEXT: Endometriosis is an estrogen-dependent disease. P38 and C-jun NH2-terminal kinase (JNK) inhibitors may have a therapeutic effect on endometriosis through regulation of prostaglandin E2 (PGE2)-induced estrogen metabolism. OBJECTIVE: The objective of this study was to determine whether the activated MAPKs signaling pathway observed in human ectopic endometrial stromal cells (ESCs) from ovarian endometriomas influences levels of aromatase and estrogen receptor β (ERβ) protein regulated by PGE2. In turn, the effects of inhibiting MAPKs in the presence of PGE2 on estrogen production were investigated in vitro and in vivo. RESULTS: Expression of aromatase and ERβ regulated by PGE2 were much higher in ESCs than eutopic ESCs from the same person. Activation of p38, JNK, ERK 1/2 and ERK 5 MAPKs by PGE2 were observed in ESCs, where PGE2-stimulated aromatase and ERβ expression mainly through p38 and JNK pathway. P38 and JNK inhibition or small interfering RNA knockdown blocked PGE2-induced aromatase and ERβ expression. PGE2 enhanced binding of downstream p38 and JNK transcription factors activating transcription factor-2 and c-Jun to aromatase and ERB promoter regions in ESCs. Moreover, treatment of endometriosis xenografts with inhibitors of p38 and JNK abrogated PGE2-amplified estradiol synthesis and xenograft growth. CONCLUSIONS: PGE2 activates p38 and JNK signaling pathways, further stimulating c-Jun and activating transcription factor-2 binding to aromatase and ERB promoter regions with elevated estradiol production. Inhibition of JNK and P38 may be a potential method of treating human endometriosis.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Aromatase Disease Models, Animal Endometriosis Estrogen Receptor beta JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinase 14 Protein Kinase Inhibitors Animals Aromatase Aromatase Aromatase Cells, Cultured Dinoprostone Dinoprostone Dinoprostone Endometriosis Endometriosis Endometriosis Endometrium Endometrium

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