期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：16
页码：6134-6139
DOI：10.1073/pnas.0400051101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
