Docetaxel has been the standard first-line chemotherapy for lethal metastatic prostate cancer (mPCa) since 2004, but resistance to docetaxel treatment is common. The molecular mechanisms of docetaxel resistance remain largely unknown and could be amenable to interventions that mitigate resistance. We have recently discovered that several docetaxel-resistant mPCa cell lines exhibit lower uptake of cellular copper and uniquely express higher levels of a copper exporter protein ATP7B. Knock-down of ATP7B by silencing RNAs (siRNAs) sensitized docetaxel resistant-mPCa cells to the growth inhibitory and apoptotic effects of docetaxel. Importantly, deletions of ATP7B in human mPCa tissues predict significantly better survival of patients after their first chemotherapy than those with wild-type ATP7B (P = 0.0006). In addition, disulfiram (DSF), an FDA-approved drug for the treatment of alcohol dependence, in combination with copper, significantly enhanced the in vivo antitumor effects of docetaxel in a docetaxel-resistant xenograft tumor model. Our analyses also revealed that DSF and copper engaged with ATP7B to decrease protein levels of COMM domain-containing protein 1 (COMMD1), S-phase kinase-associated protein 2 (Skp2), and clusterin and markedly increase protein expression of cyclin-dependent kinase inhibitor 1 (p21/WAF1). Taken together, our results indicate a copper-dependent nutrient vulnerability through ATP7B exporter in docetaxel-resistant PCa for improving the therapeutic efficacy of docetaxel.

中文翻译：

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ATP酶铜转运β（ATP7B）是提高双硫仑/铜多西紫杉醇治疗人类前列腺癌疗效的新靶点。

自 2004 年以来，多西他赛一直是致命性转移性前列腺癌 (mPCa) 的标准一线化疗，但多西他赛治疗耐药很常见。多西紫杉醇耐药的分子机制在很大程度上仍然未知，并且可能适合减轻耐药性的干预措施。我们最近发现，几种多西紫杉醇耐药的 mPCa 细胞系表现出较低的细胞铜摄取量，并且独特地表达较高水平的铜输出蛋白 ATP7B。通过沉默 RNA (siRNA) 敲低 ATP7B 可使多西紫杉醇耐药性 mPCa 细胞对多西紫杉醇的生长抑制和凋亡作用敏感。重要的是，人类 mPCa 组织中 ATP7B 的缺失预示着首次化疗后患者的生存率明显高于野生型 ATP7B 患者的生存率 (P = 0.0006)。此外，FDA批准的用于治疗酒精依赖的药物双硫仑（DSF）与铜联合使用，在多西紫杉醇耐药的异种移植肿瘤模型中显着增强了多西紫杉醇的体内抗肿瘤作用。我们的分析还表明，DSF 和铜与 ATP7B 结合，降低含 COMM 结构域的蛋白 1 (COMMD1)、S 期激酶相关蛋白 2 (Skp2) 和簇蛋白的蛋白水平，并显着增加细胞周期蛋白依赖性激酶的蛋白表达抑制剂 1 (p21/WAF1)。综上所述，我们的结果表明，多西紫杉醇耐药性 PCa 中通过 ATP7B 输出蛋白存在铜依赖性营养脆弱性，可提高多西紫杉醇的治疗效果。