Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 100, Issue 11, Pages E1404-E1414Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2015-2031
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Funding
- National Natural Science Foundation of China [81270674]
- Beijing Municipal Natural Science Foundation [7132204]
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Context: Endometriosis isanestrogen-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 beta (ER beta) 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 ER beta 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 ER beta expression mainly through p38 and JNK pathway. P38 and JNK inhibition or small interfering RNA knockdown blocked PGE2-induced aromatase and ER beta 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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