Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions

Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6134-9. doi: 10.1073/pnas.0400051101. Epub 2004 Apr 6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Base Sequence
  • Cell Line, Transformed
  • Cisplatin / pharmacology*
  • DNA Primers
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Gap Junctions / physiology*
  • Mice
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*

Substances

  • Antineoplastic Agents
  • DNA Primers
  • DNA-Binding Proteins
  • DNA-Activated Protein Kinase
  • Protein-Serine-Threonine Kinases
  • Cisplatin