Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP
Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP
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DOI：
10.1038/sj.onc.1208833
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发表时间：
2005-10-13
期刊：
影响因子：
8
通讯作者：
Cohen, MB
中科院分区：
文献类型：
--
作者：
Rokhlin, OW;Taghiyev, AF;Cohen, MB
许多研究表明，化疗药物与肿瘤坏死因子受体家族的凋亡诱导配体联合治疗是一种更有效的肿瘤治疗策略。然而，雄激素对TNFR家族诱导的前列腺癌细胞凋亡的调节作用却知之甚少。在这项研究中，我们研究了雄激素对LNCaP中肿瘤坏死因子-α和TRAIL介导的细胞凋亡的剂量依赖性影响。为了研究雄激素受体(AR)与caspase-2基因的相互作用，采用染色质免疫沉淀法，首次在体内鉴定了AR与caspase-2基因内含子8的雄激素反应元件的相互作用。我们发现DHT以剂量依赖的方式抑制细胞凋亡。在用肿瘤坏死因子-α和TRAIL治疗后，活化的Akt和caspase的激活水平之间存在着直接的、雄激素依赖性的相关性。我们还发现，雄激素对P53表达的调控至少有两种不同的机制：基因水平和蛋白质水平。同时，与LNCaP-mock细胞相比，LNCaP-si-P53细胞的AR水平更高。Se数据表明，P53和AR之间存在着相互调节的表达。我们的研究表明，雄激素依赖的凋亡治疗结果可以至少部分地通过caspase-2、Akt和P53介导的途径发生。
It has been suggested in many studies that combined treatment with chemotherapeutic agents and apoptosis-inducing ligands belonging to TNFR family is a more effective strategy for cancer treatment. However, the role of androgen regulation of TNFR family-induced apoptosis in prostate cancer is poorly understood. In this study, we investigated the dose-dependent effects of androgen on TNF-alpha and TRAIL-mediated apoptosis in LNCaP. To investigate the interaction between the androgen receptor (AR) and the caspase-2 gene, chromatin immunoprecipitation analysis was used, and we are the first to identify that AR interacts in vivo with an androgen-responsive elements in intron 8 of caspase-2 gene. We have found that DHT inhibited apoptosis in dose-dependent manner. There is a direct, androgen-dependent correlation between the levels of activated Akt and caspase activation after treatment with TNF-alpha and TRAIL. W e have also found that there are at least two different regulatory mechanisms of p53 expression by androgen: at the gene and protein levels. At the same time, the level of AR was found to be higher in LNCaP-si-p53 compared to LNCaP-mock cells. The se data indicate that there is a mutual regulation of expression between p53 and AR. Our study suggests that androgen-dependent outcome of apoptotic treatment can occur, at least in part, via the caspase-2, Akt and p53-mediated pathways.