Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin.
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.
Noguchi
Miho
M
Graduate School of Science and Technology, Chiba University, Inage-ku, Chiba 263-8522, Japan.
Yu
Dong
D
Hirayama
Ryoichi
R
Ninomiya
Yasuharu
Y
Sekine
Emiko
E
Kubota
Nobuo
N
Ando
Koichi
K
Okayasu
Ryuichi
R
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D016227:Benzoquinones / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects; D011995:Recombination, Genetic / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin