Metformin Suppresses Prostaglandin E2-Induced Cytochrome P450 Aromatase Gene Expression and Activity via Stimulation of AMP-Activated Protein Kinase in Human Endometriotic Stromal Cells
Metformin Suppresses Prostaglandin E2-Induced Cytochrome P450 Aromatase Gene Expression and Activity via Stimulation of AMP-Activated Protein Kinase in Human Endometriotic Stromal Cells
复制标题
二甲双胍通过刺激人子宫内膜异位基质细胞中 AMP 激活的蛋白激酶来抑制前列腺素 E2 诱导的细胞色素 P450 芳香酶基因表达和活性
DOI：
10.1177/1933719115590664
复制
发表时间：
2015-09-01
影响因子：
2.9
通讯作者：
Xue, Qing
中科院分区：
文献类型：
--
作者：
Zhou, Yan;Xu, Jia-Ning;Xue, Qing
背景：细胞色素P450芳香化酶（由CYP 19 A1/aromatase基因编码）在子宫内膜异位症中起重要的生理作用。已知二甲双胍可抑制前列腺素E2（PGE 2）诱导的人增生性基质细胞（ESC）中CYP 19 A1信使RNA（mRNA）表达。然而，这种抑制背后的可能机制仍有待确定。方法：在这项研究中，胚胎干细胞培养与二甲双胍，前列腺素E2，和腺苷一磷酸（AMP）激活的蛋白激酶（AMPK）抑制剂。采用定量聚合酶链反应和芳香化酶活性测定法分别测定CYP 19 A1 mRNA表达和芳香化酶活性。通过染色质免疫沉淀试验评估环AMP反应元件结合（CREB）蛋白与CYP 19 A1启动子II（PII）的结合。结果如下：我们证明二甲双胍通过刺激AMPK下调了ESCs中PGE 2刺激的芳香化酶mRNA表达（32%）和活性（25%）（4.18倍和2.14倍）。PGE 2治疗后，CREB与芳香酶PII的结合显著增加，而二甲双胍使上述刺激减弱67%。结论：二甲双胍可通过激活AMPK和抑制CREB对CYP 19 A1 PII的作用，抑制PGE 2诱导的人胚胎干细胞CYP 19 A1 mRNA表达和芳香化酶活性。本研究的结果表明，二甲双胍可能具有独特的治疗潜力，在未来作为一种抗肿瘤药物。
Background: Cytochrome P450 aromatase (encoded by the CYP19A1/aromatase gene) plays a critical physiologic role in endometriosis. Metformin is known to suppress prostaglandin E2 (PGE2)-induced CYP19A1 messenger RNA (mRNA) expression in human endometriotic stromal cells (ESCs). However, the possible mechanism behind this suppression remains to be determined. Methods: In this study, ESCs were cultured with metformin, PGE2, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitors. Expression of CYP19A1 mRNA and aromatase activity were measured by quantitative polymerase chain reaction and aromatase activity assay, respectively. The binding of the cyclic AMP response element-binding (CREB) protein to CYP19A1 promoter II (PII) was assessed by chromatin immunoprecipitation assay. Results: We demonstrated that metformin downregulated the expression of aromatase mRNA (32%) and activity (25%) stimulated by PGE2 (4.18-fold and 2.14-fold) in ESCs via stimulation of AMPK. Following PGE2 treatment, there was a marked increase in CREB binding to aromatase PII, while metformin attenuated the above-mentioned stimulation by 67%. Conclusion: Metformin could inhibit PGE2-induced CYP19A1 mRNA expression and aromatase activity via AMPK activation and inhibition of CREB to CYP19A1 PII in human ESCs. The results of the present study suggest that metformin may have unique therapeutic potential as an antiendometriotic drug in the future.