Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin

Biochem Biophys Res Commun. 2006 Dec 22;351(3):658-63. doi: 10.1016/j.bbrc.2006.10.094. Epub 2006 Oct 30.

Abstract

In order to investigate the mechanism of radio-sensitization by an Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), we studied repair of DNA double strand breaks (DSBs) in irradiated human cells pre-treated with 17-AAG. DSBs are thought to be the critical target for radiation-induced cell death. Two human tumor cell lines DU145 and SQ-5 which showed clear radio-sensitization by 17-AAG revealed a significant inhibition of DSB repair, while normal human cells which did not show radio-sensitization by the drug indicated no change in the DSB repair kinetics with 17-AAG. We further demonstrated that BRCA2 was a novel client protein for Hsp90, and 17-AAG caused the degradation of BRCA2 and in turn altered the behavior of Rad51, a critical protein for homologous recombination (HR) pathway of DSB repair. Our data demonstrate for the first time that 17-AAG inhibits the HR repair process and could provide a new therapeutic strategy to selectively result in higher tumor cell killing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / radiation effects*
  • Benzoquinones / administration & dosage*
  • Cell Line, Tumor
  • DNA Repair / drug effects*
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Lactams, Macrocyclic / administration & dosage*
  • Male
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Radiation Dosage
  • Radiation Tolerance / drug effects
  • Recombination, Genetic / drug effects*
  • Recombination, Genetic / genetics
  • Recombination, Genetic / radiation effects

Substances

  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • tanespimycin