RRC ID 42809
Author Noguchi M, Yu D, Hirayama R, Ninomiya Y, Sekine E, Kubota N, Ando K, Okayasu R.
Title Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin.
Journal Biochem Biophys Res Commun
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.
Volume 351(3)
Pages 658-63
Published 2006-12-22
DOI 10.1016/j.bbrc.2006.10.094
PII S0006-291X(06)02331-X
PMID 17083915
MeSH 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
IF 2.985
Times Cited 90
Human and Animal Cells SQ-5(RCB0110)