Metformin represses androgen-dependent and androgen-independent prostate cancers by targeting androgen receptor
Metformin represses androgen-dependent and androgen-independent prostate cancers by targeting androgen receptor
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二甲双胍通过靶向雄激素受体抑制雄激素依赖性和雄激素非依赖性前列腺癌
DOI：
10.1002/pros.23000
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发表时间：
2015-08-01
期刊：
影响因子：
2.8
通讯作者：
Jiang, Jun
中科院分区：
文献类型：
--
作者：
Wang, Yan;Liu, Gaolei;Jiang, Jun
背景：二甲双胍已被报道可抑制包括前列腺癌在内的不同类型癌症的生长。我们有兴趣了解二甲双胍对前列腺癌的作用是否具有AR依赖性，如果是，是否可以与其他抗AR药物协同作用，作为一种高效、低毒的治疗方案。方法分别采用四甲基偶氮唑盐比色法和Annexin V-FITC染色检测雄激素依赖型LNCaP和雄激素非依赖性22Rv1两种人前列腺癌细胞株单独或联合应用比卡鲁胺后的细胞存活率和细胞凋亡率。定量RT-PCR和Western blotting检测二甲双胍对AR基因和蛋白水平的影响。染色质免疫沉淀法(ChIP)证实位于AR靶基因PSA启动子区域的ARE(S)存在AR募集。结果二甲双胍处理LNCaP细胞后，细胞存活率下降，细胞凋亡率增加，联合应用二甲双胍和比卡鲁胺后，细胞存活率下降，细胞凋亡率增加，两者呈相加作用。二甲双胍下调LNCaP细胞全长AR蛋白表达。在CWR22Rv1细胞中，二甲双胍下调全长和截短AR(AR-v7)的表达。在LNCaP和CWR22Rv1细胞中，二甲双胍抑制AR信号通路不是通过影响AR蛋白的降解/稳定性，而是通过下调AR mRNAs的水平。结论二甲双胍通过靶向AR信号通路抑制前列腺癌细胞的存活并促进细胞凋亡。二甲双胍和其他抗AR药物的联合应用为前列腺癌，特别是去势耐药前列腺癌的治疗提供了一种高效、低毒、有潜力的治疗方法。前列腺癌75：1187-1196,2015。(C)2015年威利期刊公司。
BACKGROUNDMetformin has been reported to inhibit the growth of different types of cancers, including prostate cancer. We were interested to understand if the effect of metformin on prostate cancer is AR-dependent and, if so, whether metformin could act synergistically with the other anti-AR agents to serve as a therapeutic regimen with high efficacy and low toxicity.METHODSCell viabilities and apoptosis were determined by MTT assay and annexin V-FITC staining, respectively, when the two human prostate cancer cell lines, the androgen-dependent LNCaP and the androgen-independent 22RV1 were treated with metformin alone or in combination with bicalutamide. Quantitative RT-PCR and western blotting assays were conducted to examine metformin effects on AR mRNA and protein levels, respectively. Chromatin immunoprecipitation (ChIP) assays were conducted to confirm the recruitment of AR to the ARE(s) located on the promoter region of the AR target gene PSA.RESULTSMetformin treatment reduced cell viability and enhanced apoptosis for both cell lines and additive effects were observed when LNCaP cells were treated with combined metformin and bicalutamide. Metformin down-regulated full-length AR protein in LNCaP cells. Both full-length and the truncated AR (AR-v7) were down-regulated by metformin in CWR22Rv1 cells. In both LNCaP and CWR22Rv1 cells, metformin repressed AR signaling pathway not by affecting AR protein degradation/stability, but rather through down-regulating the levels of AR mRNAs.CONCLUSIONSMetformin represses prostate cancer cell viability and enhances apoptosis by targeting the AR signaling pathway. Combinations of metformin and other anti-AR agents pose a potentially promising therapeutic approach for treatment of prostate cancers, especially the castrate-resistant prostate cancer, with high efficacy and low toxicity. Prostate 75: 1187-1196, 2015. (c) 2015 Wiley Periodicals, Inc.