v‐Src oncogene causes cell transformation through its strong tyrosine kinase activity. We have revealed that v‐Src‐mediated cell transformation occurs at a low frequency and it is attributed to mitotic abnormalities‐mediated chromosome instability. v‐Src directly phosphorylates Tyr‐15 of cyclin‐dependent kinase 1 (CDK1), thereby causing mitotic slippage and reduction in Eg5 inhibitor cytotoxicity. However, it is not clear whether v‐Src modifies cytotoxicities of the other anticancer drugs targeting cell division. In this study, we found that v‐Src restores cancer cell viability reduced by various microtubule‐targeting agents (MTAs), although v‐Src does not alter cytotoxicity of DNA‐damaging anticancer drugs. v‐Src causes mitotic slippage of MTAs‐treated cells, consequently generating proliferating tetraploid cells. We further demonstrate that v‐Src also restores cell viability reduced by a polo‐like kinase 1 (PLK1) inhibitor. Interestingly, treatment with Aurora kinase inhibitor strongly induces cell death when cells express v‐Src. These results suggest that the v‐Src modifies cytotoxicities of anticancer drugs targeting cell division. Highly activated Src‐induced resistance to MTAs through mitotic slippage might have a risk to enhance the malignancy of cancer cells through the increase in chromosome instability upon chemotherapy using MTAs.

中文翻译：

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酪氨酸激酶 v-Src 改变靶向细胞分裂的抗癌药物的细胞毒性

v-Src 癌基因通过其强大的酪氨酸激酶活性引起细胞转化。我们发现 v-Src 介导的细胞转化发生频率较低，这归因于有丝分裂异常介导的染色体不稳定性。v-Src 直接磷酸化细胞周期蛋白依赖性激酶 1 (CDK1) 的 Tyr-15，从而导致有丝分裂滑移并降低 Eg5 抑制剂的细胞毒性。然而，尚不清楚 v-Src 是否会改变其他靶向细胞分裂的抗癌药物的细胞毒性。在这项研究中，我们发现 v-Src 恢复了被各种微管靶向剂 (MTA) 降低的癌细胞活力，尽管 v-Src 不会改变破坏 DNA 的抗癌药物的细胞毒性。v-Src 导致 MTA 处理的细胞有丝分裂滑动，从而产生增殖的四倍体细胞。我们进一步证明 v-Src 还可以恢复被 polo 样激酶 1 (PLK1) 抑制剂降低的细胞活力。有趣的是，当细胞表达 v-Src 时，用 Aurora 激酶抑制剂处理会强烈诱导细胞死亡。这些结果表明 v-Src 改变了靶向细胞分裂的抗癌药物的细胞毒性。通过有丝分裂滑移高度激活的 Src 诱导对 MTA 的抗性可能会通过使用 MTA 进行化疗时染色体不稳定性增加而增加癌细胞的恶性程度。