期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 25, 期 3, 页码 1677-1687出版社
WILEY
DOI: 10.1111/jcmm.16270
关键词
anti-mitotic drugs; cancer cell survival; microtubule-targeting agents; mitotic slippage; v-Src
资金
- Kyoto Pharmaceutical University Fund for the Promotion of Scientific Research
- Japan Society for the Promotion of Science [16K08253, 18K06672, 19K07055]
- Promotion and Mutual Aid Corporation for Private Schools of Japan
- Grants-in-Aid for Scientific Research [18K06672, 19K07055] Funding Source: KAKEN
v-Src alters the cytotoxicities of microtubule-targeting agents (MTAs) and polo-like kinase 1 (PLK1) inhibitor, but not DNA-damaging anticancer drugs. It induces mitotic slippage of MTAs-treated cells, leading to the generation of proliferating tetraploid cells. Treatment with Aurora kinase inhibitor strongly induces cell death in cells expressing v-Src.
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.
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