Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions
Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions
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DOI：
10.1073/pnas.0400051101
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发表时间：
2004-04-20
影响因子：
11.1
通讯作者：
Glazer, PM
中科院分区：
文献类型：
--
作者：
Jensen, R;Glazer, PM
顺铂是最广泛使用的癌症化疗药物之一，但其作用机制尚不完全清楚。目前的模型表明，顺铂的细胞杀伤是通过形成铂-DNA加合物以细胞自主的方式发生的，如果不通过DNA修复去除，则会阻断转录和复制。在这里，我们表明，有一个单独的细胞相互依赖的顺铂杀伤途径，其中受损的细胞可以传递死亡信号到邻近细胞。该信号在受损细胞内通过Ku 70、Ku 80和DNA依赖性蛋白激酶复合物的激酶功能产生，并通过间隙连接通过直接细胞间通讯传递至受体细胞。这些结果表明，DNA依赖性蛋白激酶活性和间隙连接表达在人类癌症可能会影响顺铂的临床反应。此外，与顺铂治疗结合操纵这些细胞成分的策略可能为癌症治疗提供新的方法。
Cisplatin is one of the most widely used cancer chemotherapy agents, but its mechanism of action is not fully understood. Current models suggest that cell killing by cisplatin occurs in a cell-autonomous manner by means of formation of platinum-DNA adducts that, if not removed by DNA repair, block transcription and replication. Here, we show that there is a separate cell-interdependent pathway of cisplatin killing in which damaged cells can transmit a death signal to neighboring cells. This signal is produced within the damaged cell by the kinase function of the Ku70, Ku80, and DNA-dependent protein kinase complex and is conveyed to the recipient cell by direct cell-to-cell communication through gap junctions. These findings suggest that DNA-dependent protein kinase activity and gap junction expression in human cancers may influence the clinical response to cisplatin. In addition, strategies to manipulate these cellular components in conjunction with cisplatin treatment may provide new approaches to cancer therapy.