Cyproterone acetate enhances TRAIL-induced androgen-independent prostate cancer cell apoptosis via up-regulation of death receptor 5.
Cyproterone acetate enhances TRAIL-induced androgen-independent prostate cancer cell apoptosis via up-regulation of death receptor 5.
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DOI：
10.1186/s12885-017-3153-4
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发表时间：
2017-03-07
期刊：
影响因子：
3.8
通讯作者：
Tu Y
中科院分区：
文献类型：
--
作者：
Chen L;Wolff DW;Xie Y;Lin MF;Tu Y
几乎所有的前列腺癌死亡都是由于前列腺癌细胞从最初由雄激素受体阻断诱导的细胞凋亡和/或生长抑制中逃脱后获得去势抵抗表型而发生的。肿瘤坏死因子相关凋亡诱导配体（TNF-related apoptosis-inducing ligand，TRAIL）对正常细胞毒性小，对肿瘤细胞具有明显的凋亡活性，是一种很有吸引力的肿瘤治疗药物。然而，包括前列腺癌在内的大多数局部癌症对TRAIL诱导的细胞凋亡具有抗性，从而产生了在癌细胞中诱导TRAIL敏感性的治疗挑战。本文报道了醋酸环丙孕酮（一种抗雄激素类固醇）对雄激素受体阴性前列腺癌细胞TRAIL诱导的凋亡的影响。膜联蛋白V/碘化丙啶标记和聚（ADP-核糖）聚合酶裂解试验评估细胞凋亡。通过实时定量PCR和蛋白质印迹分析确定基因和蛋白质表达变化。用荧光素酶报告基因检测醋酸环丙孕酮对基因启动子活性的影响。醋酸环丙孕酮而不是AR拮抗剂比卡鲁胺显著增加雄激素受体阴性的人前列腺癌PC-3和DU 145细胞对TRAIL诱导的凋亡的易感性，但对永生化的人前列腺基质PS30细胞和人胚肾HEK 293细胞没有影响。对TRAIL诱导的凋亡途径的进一步研究表明，醋酸环丙孕酮通过选择性增加死亡受体5（DR 5）mRNA和蛋白表达发挥其作用。醋酸环丙孕酮处理也增加了DR 5基因启动子的活性，这可以通过突变DR 5基因启动子中转录因子CCAAT-增强子结合蛋白同源蛋白（CHOP）的共有结合结构域来消除。醋酸环丙孕酮以浓度和时间依赖性方式增加CHOP表达，内质网应激抑制剂4-苯基丁酸酯可阻断醋酸环丙孕酮诱导的CHOP和DR 5上调。更重要的是，CHOP的siRNA沉默显著降低了前列腺癌细胞中醋酸环丙孕酮诱导的DR 5上调和TRAIL敏感性。我们的研究显示了醋酸环丙孕酮对前列腺癌细胞凋亡途径的新作用，并提出了肿瘤坏死因子相关凋亡配体（TRAIL）与醋酸环丙孕酮联合使用可能成为治疗去势抵抗性前列腺癌的有希望的策略的可能性。本文的在线版本（doi：10.1186/s12885-017-3153-4）包含补充材料，可供授权用户使用。
Virtually all prostate cancer deaths occur due to obtaining the castration-resistant phenotype after prostate cancer cells escaped from apoptosis and/or growth suppression initially induced by androgen receptor blockade. TNF-related apoptosis-inducing ligand (TRAIL) was an attractive cancer therapeutic agent due to its minimal toxicity to normal cells and remarkable apoptotic activity in tumor cells. However, most localized cancers including prostate cancer are resistant to TRAIL-induced apoptosis, thereby creating a therapeutic challenge of inducing TRAIL sensitivity in cancer cells. Herein the effects of cyproterone acetate, an antiandrogen steroid, on the TRAIL-induced apoptosis of androgen receptor-negative prostate cancer cells are reported. Cell apoptosis was assessed by both annexin V/propidium iodide labeling and poly (ADP-ribose) polymerase cleavage assays. Gene and protein expression changes were determined by quantitative real-time PCR and western blot assays. The effect of cyproterone acetate on gene promoter activity was determined by luciferase reporter assay. Cyproterone acetate but not AR antagonist bicalutamide dramatically increased the susceptibility of androgen receptor-negative human prostate cancer PC-3 and DU145 cells to TRAIL-induced apoptosis but no effects on immortalized human prostate stromal PS30 cells and human embryonic kidney HEK293 cells. Further investigation of the TRAIL-induced apoptosis pathway revealed that cyproterone acetate exerted its effect by selectively increasing death receptor 5 (DR5) mRNA and protein expression. Cyproterone acetate treatment also increased DR5 gene promoter activity, which could be abolished by mutation of a consensus binding domain of transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP) in the DR5 gene promoter. Cyproterone acetate increases CHOP expression in a concentration and time-dependent manner and endoplasmic reticulum stress reducer 4-phenylbutyrate could block cyproterone acetate-induced CHOP and DR5 up-regulation. More importantly, siRNA silencing of CHOP significantly reduced cyproterone acetate-induced DR5 up-regulation and TRAIL sensitivity in prostate cancer cells. Our study shows a novel effect of cyproterone acetate on apoptosis pathways in prostate cancer cells and raises the possibility that a combination of TRAIL with cyproterone acetate could be a promising strategy for treating castration-resistant prostate cancer. The online version of this article (doi:10.1186/s12885-017-3153-4) contains supplementary material, which is available to authorized users.