Department of Urology, Ruijin hospital, Shanghai Jiaotong University, school of medicine Shanghai, China.
Am J Transl Res. 2013 Apr 19;5(3):359-67. Print 2013.
The palliative therapy effect by docetaxel for CRPC patients makes it urgent to improve the therapy. It was suggested that PI3K and androgen receptor-directed combination therapy may be effective for prostate cancer (PCa) patients PTEN negative. However, for those patients PTEN positive, the mechanism of anti-apoptosis survival of cancer cells is not yet well defined. Amplification of AURKA has been detected in 5% of PCa. In this work, Du145, a PTEN positive PCa cell model, was employed to investigate the role of aurora kinase a (AURKA) on cell growth. Inhibition of AURKA expression by shRNA markedly reduced prostate cancer cell viability. Furthermore, we demonstrate that AURKA inhibition induced a remarkable downregulation of AKT activity and Bax induction. Moreover, specific inhibition of the activity of AURKA, but not other aurora family members, by small molecular chemical inhibitors induced significant cell killing effects. Notably, AURKA inhibition sensitized prostate cancer cells to docetaxel treatment. Our work suggests that AURKA-directed monotherapy or combination therapy with docetaxel could be a potent treatment for PCa patients in future.
多西紫杉醇治疗 CRPC 的姑息疗法效果迫切需要改善。有研究表明，PI3K 和雄激素受体靶向联合治疗可能对 PTEN 阴性的前列腺癌（PCa）患者有效。然而，对于那些 PTEN 阳性的患者，癌细胞抗凋亡生存的机制尚不清楚。在 5%的 PCa 中检测到 AURKA 的扩增。在这项工作中，我们使用了 PTEN 阳性的前列腺癌细胞模型 Du145，来研究 Aurora 激酶 A（AURKA）对细胞生长的作用。通过 shRNA 抑制 AURKA 的表达显著降低了前列腺癌细胞的活力。此外，我们证明 AURKA 抑制诱导了 AKT 活性的显著下调和 Bax 的诱导。此外，通过小分子化学抑制剂特异性抑制 AURKA 的活性，而不是其他 Aurora 家族成员，可诱导显著的细胞杀伤作用。值得注意的是，AURKA 抑制使前列腺癌细胞对多西紫杉醇治疗敏感。我们的工作表明，AURKA 定向单药治疗或与多西紫杉醇联合治疗可能是未来治疗 PCa 患者的有效方法。
