Department of Oncology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450053, Henan, China.
Department of Oncology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450053, Henan, China.
Arch Biochem Biophys. 2023 Mar 15;737:109551. doi: 10.1016/j.abb.2023.109551. Epub 2023 Feb 21.
Docetaxel is a first-line chemotherapy drug for castration-resistant prostate cancer (CRPC); yet, some CRPC patients develop docetaxel drug resistance. Cabazitaxel is approved in the post-docetaxel treatment setting. However, recent studies suggested cross-resistance between the development of drug resistance and current treatments. In this study, we used docetaxel-resistant cell lines DU145/DTX50 and PC-3/DTX30 to measure the responses to cabazitaxel. Our findings demonstrated that docetaxel resistance could lead to cross-resistance to cabazitaxel. After docetaxel-resistant cells were treated with cabazitaxel, transcriptome analysis was performed, and the results were analyzed in combination with survival analysis and correlation analysis with Gleason score to screen the cross-resistance genes. The continuously increased expression of kinesin family member 14 (KIF14) was identified as the main cause of cross-resistance to cabazitaxel in docetaxel-resistant cells. Silencing the expression of KIF14 could restore the sensitivity of resistant PCa cells to docetaxel and cabazitaxel, attenuate proliferation and promote apoptosis of the resistant PCa cells. Notably, the depressed expression of KIF14 inhibited the phosphorylation of Akt located downstream. In summary, KIF14 mediates the cross-resistance between docetaxel and cabazitaxel, and targeting KIF14 could be an effective measurement for reversing docetaxel or cabazitaxel chemotherapy failure or enhancing the anti-tumor effects of docetaxel or cabazitaxel.
多西他赛是一种用于去势抵抗性前列腺癌（CRPC）的一线化疗药物；然而，一些 CRPC 患者会产生多西他赛耐药性。卡巴他赛已被批准用于多西他赛治疗后的治疗环境中。然而，最近的研究表明，在耐药性的发展和当前治疗之间存在交叉耐药性。在这项研究中，我们使用多西他赛耐药细胞系 DU145/DTX50 和 PC-3/DTX30 来测量对卡巴他赛的反应。我们的研究结果表明，多西他赛耐药性可能导致对卡巴他赛的交叉耐药性。在多西他赛耐药细胞用卡巴他赛处理后，进行转录组分析，并结合生存分析和与 Gleason 评分的相关性分析来筛选交叉耐药基因。发现驱动蛋白家族成员 14（KIF14）的持续高表达是多西他赛耐药细胞对卡巴他赛交叉耐药的主要原因。沉默 KIF14 的表达可以恢复耐药 PCa 细胞对多西他赛和卡巴他赛的敏感性，减弱耐药 PCa 细胞的增殖并促进其凋亡。值得注意的是，KIF14 的表达下调抑制了 Akt 的下游磷酸化。综上所述，KIF14 介导了多西他赛和卡巴他赛之间的交叉耐药性，靶向 KIF14 可能是逆转多西他赛或卡巴他赛化疗失败或增强多西他赛或卡巴他赛抗肿瘤作用的有效措施。
