Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer.
Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer.
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DOI：
10.1158/0008-5472.can-11-1417
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发表时间：
2011-09-15
期刊：
影响因子：
11.2
通讯作者：
Giannakakou P
中科院分区：
文献类型：
--
作者：
Darshan MS;Loftus MS;Thadani-Mulero M;Levy BP;Escuin D;Zhou XK;Gjyrezi A;Chanel-Vos C;Shen R;Tagawa ST;Bander NH;Nanus DM;Giannakakou P
前列腺癌进展需要主动雄激素受体（AR）信号传导，其发生在AR从细胞质易位到细胞核之后。紫杉烷类化疗可提高去势抵抗性前列腺癌（CRPC）患者的生存率。紫杉烷类诱导微管稳定，有丝分裂停滞和凋亡细胞死亡，但最近的数据表明紫杉烷类也可以影响AR信号。在这里，我们报告紫杉烷抑制配体诱导的AR核转位和下游的AR靶基因，如PSA的转录激活。在具有获得性β-微管蛋白突变的细胞中，AR核转位未被抑制，该突变阻止了紫杉烷诱导的微管稳定化，证实了微管在AR运输中的作用。在配体激活后，AR与负端微管运动动力蛋白结合，从而在微管上运输并易位到细胞核。从接受紫杉烷化疗的CRPC患者的外周血中分离的循环肿瘤细胞（CTC）的分析揭示了AR胞质隔离与对治疗的临床反应之间的显著相关性。这些结果表明，紫杉烷类化合物至少部分通过抑制AR核转运和信号传导作用于CRPC患者。此外，他们建议监测CRPC患者CTC中的AR亚细胞定位可能预测对紫杉烷化疗的临床反应。
Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest and apoptotic cell death, but recent data suggest taxanes can also affect AR signaling. Here we report that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as PSA. AR nuclear translocation was not inhibitied in cells with acquired β-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTCs) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy.