Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer.
Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer.
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DOI：
10.18632/oncotarget.21147
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发表时间：
2017-10-20
期刊：
影响因子：
--
通讯作者：
Oya M
中科院分区：
文献类型：
--
作者：
Kosaka T;Hongo H;Miyazaki Y;Nishimoto K;Miyajima A;Oya M
紫杉烷诱导的肿瘤细胞内活性氧（ROS）的产生可能影响紫杉烷诱导的细胞死亡或耐药。我们研究了紫杉烷类化合物的细胞毒性作用与人去势抵抗性前列腺癌（CRPC）细胞系中ROS产生之间的相关性。在体外用递增浓度的多西他赛或卡巴他赛处理三种人前列腺癌细胞系。卡巴他赛在人CRPC细胞中显示出比多西他赛显著更高的细胞毒性功效，伴随着通过FACS分析检测到的升高的ROS产生。为了研究卡巴他赛介导的细胞死亡是否由卡巴他赛诱导的ROS产生引起，我们在抗氧化剂NAC存在下处理CRPC细胞。NAC可降低卡巴他赛诱导的细胞毒性作用。我们发现，卡巴他赛可显著抑制Sestrin-3（SESN 3）清除ROS，但多西他赛不抑制。这些结果表明，与多西他赛相比，人CRPC对卡巴他赛的敏感性更高，涉及通过抑制抗氧化酶SESN 3的表达产生ROS。
Reactive oxygen species (ROS) production induced by taxanes in cancer cells may influence the taxane-induced cell death or the drug resistance. We investigated the correlation between the cytotoxic effect of taxanes and ROS production in human castration-resistant prostate cancer (CRPC) cell lines. Three human prostate cancer cell lines were treated with increasing concentrations of docetaxel or cabazitaxel in vitro. Cabazitaxel showed significantly higher cytotoxic efficacy than docetaxel in human CRPC cells, accompanied by elevated ROS production detected by FACS analysis. To investigate whether cabazitaxel-mediated cell death was caused by the ROS generation induced by cabazitaxel, we treated CRPC cells in the presence of antioxidant NAC. NAC reduced the cytotoxic effect induced by cabazitaxel. We found that ROS elimination by Sestrin-3 (SESN3) was significantly inhibited by cabazitaxel, but not by docetaxel. These results indicate higher sensitivity of human CRPC to cabazitaxel compared to docetaxel involves ROS production through inhibiting the expression of antioxidant enzyme SESN3.
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