Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer.
Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer.
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DOI：
10.1158/0008-5472.can-10-0585
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Kyprianou N
中科院分区：
文献类型：
--
作者：
Zhu ML;Horbinski CM;Garzotto M;Qian DZ;Beer TM;Kyprianou N
最近对雄激素受体（AR）活性调节的认识导致了前列腺癌患者AR功能的新治疗靶向。多西他赛是一种被批准用于治疗去势抵抗性前列腺癌（CRPC）的化疗药物，但这种微管蛋白靶向药物的作用机制尚不完全清楚。本研究探讨了微管和细胞骨架对雄激素介导的信号传导的贡献，以及它们对人类前列腺癌中AR活性的抑制的后果。比较分析多西他赛治疗和未治疗的前列腺癌患者的组织微阵列（TMA）的前列腺特异性抗原（PSA）和AR免疫反应性。基于PSA mRNA表达和雄激素反应元件（ARE）报告活性，在体外前列腺癌细胞中测定AR转录活性。用免疫沉淀和免疫荧光法检测AR与微管蛋白的相互作用。用多西他赛治疗前列腺癌患者导致AR显著易位。在未治疗的标本中，50%的前列腺肿瘤细胞显示出AR的核积聚，而多西他赛治疗的肿瘤具有显著耗尽的核AR（38%），胞质AR增加。AR核定位与PSA表达相关。在体外，前列腺癌细胞暴露于Paclitaxel（1μM）或Nocodazole（5μg/ml），通过靶向与微管蛋白相关的AR，抑制雄激素依赖性AR核转位。截短AR的引入表明AR-微管蛋白相互作用的N-末端结构域的要求。我们的研究结果表明，除了阻断细胞分裂外，多西他赛还损害AR信号传导，这一证据使人们对微管靶向药物在前列腺癌中的治疗效果有了新的认识。
Recent insights into the regulation of the androgen receptor (AR) activity led to novel therapeutic targeting of AR function in prostate cancer patients. Docetaxel is an approved chemotherapy for treatment of castration-resistant-prostate cancer (CRPC), but the mechanism underlying the action of this tubulin-targeting drug is not fully understood. This study investigates the contribution of microtubules and the cytoskeleton to androgen-mediated signaling, and the consequences of their inhibition on AR activity in human prostate cancer. Tissue microarrays (TMAs) from Docetaxel-treated and untreated prostate cancer patients were comparatively analyzed for prostate specific antigen (PSA) and AR immunoreactivity. The AR transcriptional activity was determined in prostate cancer cells in vitro, based on PSA mRNA expression and the androgen-response element (ARE) reporter activity. The interaction of AR with tubulin was examined by immunoprecipitation and immunofluorescence. Treatment of prostate cancer patients with Docetaxel led to a significant translocation of AR. In untreated specimens, 50% prostate tumor cells exhibited nuclear accumulation of AR, compared to Docetaxel-treated tumors that had significantly depleted nuclear AR (38%), paralleled by an increase in cytosolic AR. AR nuclear localization correlated with PSA expression. In vitro, exposure of prostate cancer cells to Paclitaxel (1μM) or Nocodazole (5μg/ml), inhibited androgen-dependent AR nuclear translocation, by targeting AR association with tubulin. Introduction of a truncated AR indicated the requirement of the N-terminal domain for AR-tubulin interaction. Our findings demonstrate that in addition to blocking cell division, Docetaxel impairs AR signaling, evidence that enables new insights into the therapeutic efficacy of microtubule-targeting drugs in prostate cancer.