|Metformin Inhibits StAR Expression in Human Endometriotic Stromal Cells via AMPK-Mediated Disruption of CREB-CRTC2 Complex Formation|
|Xu, Jia-Ning; Zeng, Cheng; Zhou, Yan; Peng, Chao; Zhou, Ying-Fang; Xue, Qing|
|刊名||JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM|
|WOS标题词||Science & Technology|
|类目[WOS]||Endocrinology & Metabolism|
|研究领域[WOS]||Endocrinology & Metabolism|
|关键词[WOS]||ACUTE REGULATORY PROTEIN ; ELEMENT-BINDING PROTEIN ; STEROIDOGENIC-FACTOR-I ; AROMATASE EXPRESSION ; ACTIVATION ; BREAST ; CREB ; PROLIFERATION ; TRANSCRIPTION ; COACTIVATORS|
Context: Endometriosis is an estrogen-dependent disease affecting reproductive women. Metformin could have a therapeutic effect on endometriosis through regulation of local estrogen production.
Objects: The aim of this study was to investigate the molecular and cellular mechanism by which metformin regulates StAR expression in human endometriotic stromal cells (ESCs).
Methods: ESCs derived from ovarian endometriomas were cultured with metformin and prostaglandin E2 (PGE2). StAR mRNA was measured by quantitative PCR; pregnenolone, progesterone, and estrogen production were measured by ELISA kits; steroidogenic acute regulatory protein (StAR), AMP-activated protein kinase, cAMP response element binding protein (CREB), and CREB-regulated transcription coactivator 2 (CRTC2) protein expression were measured by Western blot assay; and CRTC2 translocation and its association with CREB were assessed by coimmunoprecipitation assay and CRTC2-CREB complex binding by a chromatin immunoprecipitation assay.
Results: 1) StAR mRNA levels in ESCs are 264 times higher than those in endometrial cells. 2) Metformin downregulates the StAR mRNA expression (maximum 31.7%) stimulated by PGE2 (2.4-fold) in ESCs. 3) PGE2 induces CRTC2 translocation and enhances its association with CREB to form a transcription complex that binds to the StAR promoter region. 4) Metformin prevents the nuclear translocation of CRTC2 by increasing AMP-activated protein kinase phosphorylation. This inhibits transcription of StAR by disrupting formation of the CREB-CRTC2 complex, involved in activation of the StAR promoter cAMP response element.
Conclusions: We have demonstrated a detailed mechanistic analysis of StAR expression regulated by metformin in ESCs. Our data highlight a role for CRTC2 in the mechanism by which metformin inhibits StAR expression.
|项目编号||81270674 ; 7132204|
|资助机构||National Natural Science Foundation of China ; Natural Science Foundation of Beijing, China|
|作者单位||Peking Univ, Hosp 1, Dept Obstet & Gynecol, Beijing 100034, Peoples R China|
|Xu, Jia-Ning,Zeng, Cheng,Zhou, Yan,et al. Metformin Inhibits StAR Expression in Human Endometriotic Stromal Cells via AMPK-Mediated Disruption of CREB-CRTC2 Complex Formation[J]. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM,2014,99(8):2795-2803.|
|APA||Xu, Jia-Ning,Zeng, Cheng,Zhou, Yan,Peng, Chao,Zhou, Ying-Fang,&Xue, Qing.(2014).Metformin Inhibits StAR Expression in Human Endometriotic Stromal Cells via AMPK-Mediated Disruption of CREB-CRTC2 Complex Formation.JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM,99(8),2795-2803.|
|MLA||Xu, Jia-Ning,et al."Metformin Inhibits StAR Expression in Human Endometriotic Stromal Cells via AMPK-Mediated Disruption of CREB-CRTC2 Complex Formation".JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 99.8(2014):2795-2803.|