C-Jun NH2-Terminal Kinase and p38 Inhibition Suppresses Prostaglandin E2-Stimulated Aromatase and Estrogen Receptor Levels in Human Endometriosis.
C-Jun NH2-Terminal Kinase and p38 Inhibition Suppresses Prostaglandin E2-Stimulated Aromatase and Estrogen Receptor Levels in Human Endometriosis.
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DOI：
10.1210/jc.2015-2031
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
C. Zeng;Jia-ning Xu;Yan Zhou;Huixia Yang;Yingqiao Zhou;Q. Xue
中科院分区：
文献类型：
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作者：
C. Zeng;Jia-ning Xu;Yan Zhou;Huixia Yang;Yingqiao Zhou;Q. Xue
子宫内膜异位症是一种雌激素依赖性疾病。P38和C-jun氨基末端激酶（JNK）抑制剂可能通过调节前列腺素E2（PGE 2）诱导的雌激素代谢而对子宫内膜异位症产生治疗作用。目的探讨卵巢恶性肿瘤异位子宫内膜间质细胞（ESCs）中MAPKs信号通路的激活是否影响PGE 2调控的芳香化酶和雌激素受体β（ERβ）蛋白水平。反过来，在体外和体内研究了在PGE 2存在下抑制MAPK对雌激素产生的影响。结果同一个体ESCs中芳香化酶和ERβ的表达受PGE 2的调控，其表达水平明显高于正常ESCs。PGE 2可激活p38、JNK、ERK 1/2和ERK 5 MAPK，主要通过p38和JNK途径激活芳香化酶和ERβ的表达。P38和JNK抑制或小干扰RNA敲低可阻断PGE 2诱导的芳香化酶和ERβ表达。PGE 2增强了下游p38和JNK转录因子激活转录因子-2和c-Jun与ESCs中芳香酶和ERB启动子区域的结合。此外，用p38和JNK抑制剂治疗子宫内膜异位症异种移植物可抑制PGE 2扩增的雌二醇合成和异种移植物生长。结论PGE 2激活p38和JNK信号通路，进一步刺激c-Jun和激活转录因子2与芳香化酶和ERB启动子区域的结合，从而增加雌二醇的产生。抑制JNK和P38可能是治疗子宫内膜异位症的一种潜在方法。
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.