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

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.

Authors:
 [1];  [2];  [3];  [3];  [3];  [3];  [4];  [1];  [2];  [5]
  1. Graduate School of Science and Technology, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
  2. (Japan)
  3. Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan)
  4. Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan)
  5. Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 (Japan). E-mail: rokayasu@nirs.go.jp
Publication Date:
OSTI Identifier:
20857926
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 351; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2006.10.094; PII: S0006-291X(06)02331-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; APOPTOSIS; DNA REPAIR; GENETIC RADIATION EFFECTS; INHIBITION; IRRADIATION; PROTEINS; RECOMBINATION; STRAND BREAKS; TUMOR CELLS

Citation Formats

Noguchi, Miho, Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Yu, Dong, Hirayama, Ryoichi, Ninomiya, Yasuharu, Sekine, Emiko, Kubota, Nobuo, Ando, Koichi, Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, and Okayasu, Ryuichi. Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2006.10.094.
Noguchi, Miho, Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Yu, Dong, Hirayama, Ryoichi, Ninomiya, Yasuharu, Sekine, Emiko, Kubota, Nobuo, Ando, Koichi, Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, & Okayasu, Ryuichi. Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. United States. doi:10.1016/j.bbrc.2006.10.094.
Noguchi, Miho, Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Yu, Dong, Hirayama, Ryoichi, Ninomiya, Yasuharu, Sekine, Emiko, Kubota, Nobuo, Ando, Koichi, Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, and Okayasu, Ryuichi. Fri . "Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin". United States. doi:10.1016/j.bbrc.2006.10.094.
@article{osti_20857926,
title = {Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin},
author = {Noguchi, Miho and Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 and Yu, Dong and Hirayama, Ryoichi and Ninomiya, Yasuharu and Sekine, Emiko and Kubota, Nobuo and Ando, Koichi and Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555 and Okayasu, Ryuichi},
abstractNote = {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.},
doi = {10.1016/j.bbrc.2006.10.094},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 351,
place = {United States},
year = {Fri Dec 22 00:00:00 EST 2006},
month = {Fri Dec 22 00:00:00 EST 2006}
}