George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14642, USA; Biology Department, University of Rochester, Rochester, NY, USA.
Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, Tianjin Medical University, Tianjin, 300211, China.
Cancer Lett. 2019 Mar 1;444:35-44. doi: 10.1016/j.canlet.2018.09.025. Epub 2018 Sep 21.
Chemotherapy with docetaxel remains the effective therapy to suppress castration resistant prostate cancer (CRPC) in some patients. However, most chemotherapy with docetaxel eventually fails with the development of docetaxel resistance after 18-weeks of treatment. Here we found docetaxel treatment might have an adverse effect of increasing the androgen receptor (AR) protein level in the CRPC cells, and combining docetaxel with anti-AR therapy using AR-shRNA or the AR degradation enhancer ASC-J9® may increase docetaxel sensitivity to better suppress the CRPC cell growth. Mechanism dissection found docetaxel might have the adverse effect of increasing the AR protein stability via suppressing the AR ubiquitination due to the increased AR phosphorylation. The consequence of such increased AR protein may then lead to increase p21 expression via transcriptional regulation. Preclinical studies with in vitro cells lines also demonstrated that targeting AR with ASC-J9® led to suppressing the AR-increased p21 expression to improve the docetaxel sensitivity in the CRPC cells that already developed docetaxel resistance. Together, these results suggest that a combined therapy of docetaxel and ASC-J9® is a novel therapy to better suppress CRPC in patients that already developed docetaxel resistance.
多西紫杉醇化疗仍然是抑制一些患者去势抵抗性前列腺癌（CRPC）的有效疗法。然而，大多数多西紫杉醇化疗最终会失败，因为在治疗 18 周后会产生多西紫杉醇耐药性。在这里，我们发现多西紫杉醇治疗可能会对 CRPC 细胞中的雄激素受体（AR）蛋白水平产生不利影响，并且将多西紫杉醇与使用 AR-shRNA 或 AR 降解增强剂 ASC-J9®的抗 AR 治疗联合使用可能会增加多西紫杉醇的敏感性，从而更好地抑制 CRPC 细胞的生长。机制分析发现，由于 AR 磷酸化增加，多西紫杉醇可能会通过抑制 AR 泛素化而产生增加 AR 蛋白稳定性的不利影响。这种增加的 AR 蛋白的后果可能会导致通过转录调节增加 p21 的表达。体外细胞系的临床前研究也表明，使用 ASC-J9®靶向 AR 可抑制 AR 增加的 p21 表达，从而提高已经对多西紫杉醇产生耐药性的 CRPC 细胞对多西紫杉醇的敏感性。总之，这些结果表明，多西紫杉醇和 ASC-J9®联合治疗是一种新的治疗方法，可以更好地抑制已经对多西紫杉醇产生耐药性的患者的 CRPC。
