title: Heat shock protein 90 (Hsp90) chaperone complex inhibitor, radicicol, potentiated radiation-induced cell killing in a hormone-sensitive prostate cancer cell line through degradation of the androgen receptor.
abstract: Until now, there has not been enough information on how androgens or androgen deprivation may influence the response of cancer cells to radiation. In this study, the effect of dihydrotestosterone (DHT) on cellular proliferative activity and radiosensitivity was examined in a hormone-sensitive human prostate cancer cell line, LNCaP. In addition, the study also examined how a heat shock protein 90 (Hsp90) chaperone complex inhibitor modified the effect of DHT on the radiosensitivity of the cells, because binding of the androgen receptor (AR) to Hsp90 is required to maintain the stability and functioning of AR. The hormone-sensitive human prostate cancer cell line, LNCaP, was used. Radicicol was used as one of the known Hsp90 chaperone complex inhibitors, and the cells were incubated in the presence of this compound at a concentration of 500 nM. Cellular radiosensitivity was determined by the clonogenic assay; the changes in the protein expression were examined by Western blotting or immunofluorescence. DHT at a concentration of 1 nM caused enhancement of the proliferative activity and reduction of the radiosensitivity of the cells. Radicicol at a concentration of 500 nM abolished the DHT-induced decrease in cellular radiosensitivity and potentiated the radiation-induced cell killing synergistically. Consistent with the changes in the cellular radiosensitivity, radicicol degraded AR, Raf-1 and HER2/neu via reduced binding of AR to Hsp90, although selective degradation of HER2/neu caused by Herceptin, a monoclonal antibody against HER2, did not affect the cellular radiosensitivity. The results suggest that the Hsp9O chaperone complex may be a potential molecular target for potentiation of radiation-induced cell killing in a hormone-sensitive prostate cancer cell line.
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Harashima
authors.forename: T
authors.initials: T
authors.lastname: Akimoto
authors.forename: T
authors.initials: T
authors.lastname: Nonaka
authors.forename: K
authors.initials: K
authors.lastname: Tsuzuki
authors.forename: N
authors.initials: N
authors.lastname: Mitsuhashi
authors.forename: T
authors.initials: T
authors.lastname: Nakano
mesh_terms: D000728:Androgens / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects* / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000187:drug effects*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D008297:Male; D018832:Molecular Chaperones / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000187:drug effects
chemical_list: D000728:Androgens; D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D018942:Macrolides; D018832:Molecular Chaperones; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; C035359:monorden