Department of Urology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Jinan, 250014, People's Republic of China.
Department of Out-Patient, No. 88 Hospital of PLA, Tai'an, 271000, People's Republic of China.
Cancer Chemother Pharmacol. 2018 Jun;81(6):999-1006. doi: 10.1007/s00280-018-3578-8. Epub 2018 Mar 31.
PURPOSE: At least to date, no effective treatment for advanced castration-resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive. METHODS: In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC. RESULTS: Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment. CONCLUSIONS: In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim-dependent manner. Furthermore, additionally targeting Cdc20 might be a promising solution for the treatment of the CRPC with docetaxel resistance.
目的：迄今为止，尚无针对晚期去势抵抗性前列腺癌（CRPC）的有效治疗方法。最近的研究表明，细胞分裂周期 20 同源物（Cdc20）的过表达与去势抵抗性前列腺癌患者的预后不良相关。然而，Cdc20 在 CRPC 中对多西他赛耐药的发展中的作用机制仍不清楚。
方法：在这项研究中，在三个独立的源自不同组织的 CRPC 细胞系（LNCaP、PC3 和 DU145）中证实了 Cdc20 的转录。在 DU145 和 PC3 的背景下生成了多西他赛耐药（DR）细胞系。在野生型和 DR 细胞系中检测 Cdc20 和 Bcl-2 相互作用细胞死亡介体（Bim）的蛋白水平。为了进一步探讨 Cdc20 过表达的机制，生成了 Cdc20 或 Bim 剥夺的稳定细胞系，并检查了其生物学参数。此外，在 DR 细胞系中使用了一种特定的 Cdc20 抑制剂，以探索治疗多西他赛耐药性 CRPC 的潜在方法。
结果：在这里，我们确定了 Cdc20 在多西他赛耐药性 CRPC 细胞系（包括 LNCaP、PC3 和 DU145）中过表达。我们还报告说，DR 细胞系（模拟多西他赛治疗后复发性前列腺癌细胞）与 CRPC 细胞系相比，Cdc20 蛋白水平更高。有趣的是，与野生型相比，DR 细胞系中 Cdc20 的 E3 连接酶底物 Bim 的蛋白水平降低，而 mRNA 水平相似。更重要的是，在 DR 细胞系中，Cdc20 缺失诱导的生物学表型可以通过 Bim 的额外敲低显著逆转。结果，用药理学 Cdc20 抑制剂处理的多西他赛耐药性前列腺癌细胞对多西他赛治疗变得敏感。
结论：总之，我们的数据共同表明，Cdc20 过表达以 Bim 依赖的方式促进了 CRPC 细胞系的多西他赛耐药性。此外，额外靶向 Cdc20 可能是治疗多西他赛耐药性 CRPC 的一种有前途的方法。
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