Copper enhances genotoxic drug resistance via ATOX1 activated DNA damage repair
Copper enhances genotoxic drug resistance via ATOX1 activated DNA damage repair
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DOI：
10.1016/j.canlet.2022.215651
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发表时间：
2022-03-21
期刊：
影响因子：
9.7
通讯作者：
Teng, Chun-Bo
中科院分区：
文献类型：
--
作者：
Jin, Jing;Ma, Mingjun;Teng, Chun-Bo
铜参与多种生物化学和生理过程。吸收的铜离子通过铜伴侣（如ATOX1）转运到细胞内目的地。先前的研究表明，肿瘤细胞对铜有很高的需求；然而，其在癌细胞中的作用尚未完全阐明。在这里，我们揭示了高水平的铜至少部分通过atox1诱导MDC1（一种参与双链DNA损伤修复的关键蛋白）的表达，有助于癌细胞的耐药和受损DNA的修复。具体来说，ATOX1在各种基因毒性药物处理后进入细胞核靶向MDC1启动子，从而以铜依赖的方式促进MDC1的转录。因此，敲除或阻断ATOX1使移植瘤小鼠模型对吉西他滨敏感。总之，我们的发现对铜在DNA损伤修复中的作用有了新的认识，并为耐药癌症的临床癌症治疗提供了新的策略。
Copper is involved in various biochemical and physiological processes. The absorbed copper ions are transported to the intracellular destination via copper chaperones, such as ATOX1. Previous studies have demonstrated that neoplastic cells have a high demand for copper; however, its role in cancer cells has not been fully elucidated. Here, we reveal that the high level of copper contributes to drug resistance and repair of damaged DNA in cancer cells at least partially via ATOX1induced expression of MDC1, a crucial protein involved in double-strand DNA damage repair. Specifically, ATOX1 enters into nuclear to target MDC1 promoter after treatments of various genotoxic agents, thus promoting the transcription of MDC1 in a copper-dependent manner. Therefore, knockout or blockage of ATOX1 conferred sensitivity to Gemcitabine in transplanted tumor mouse models. Together, our findings gain new insight into the role of copper in DNA damage repair and provide a novel strategy for clinical cancer therapy of drug-resistance cancers.