Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions.
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.
Jensen
Ryan
R
Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040, USA.
Glazer
Peter M
PM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000494:pharmacology*; D017931:DNA Primers; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D017629:Gap Junctions / Q000502:physiology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin