Depletion of the type 1 IGF receptor delays repair of radiation-induced DNA double strand breaks.
Radiother Oncol
; 103(3): 402-9, 2012 Jun.
Article
em En
| MEDLINE
| ID: mdl-22551565
ABSTRACT
BACKGROUND AND PURPOSE:
IGF-1R depletion sensitizes prostate cancer cells to ionizing radiation and DNA-damaging cytotoxic drugs. This study investigated the hypothesis that IGF-1R regulates DNA double strand break (DSB) repair.METHODS:
We tested effects of IGF-1R siRNA transfection on the repair of radiation-induced DSBs by immunoblotting and immunofluorescence for γH2AX, and pulsed-field gel electrophoresis. Homologous recombination (HR) was quantified by reporter assays, and cell cycle distribution by flow cytometry.RESULTS:
We confirmed that IGF-1R depletion sensitized DU145 and PC3 prostate cancer cells to ionizing radiation. DU145 control transfectants resolved radiation-induced DSBs within 24 h, while IGF-1R depleted cells contained 30-40% unrepaired breaks at 24 h. IGF-1R depletion induced significant reduction in DSB repair by HR, although the magnitude of the repair defect suggests additional contributory factors. Radiation-induced G2-M arrest was attenuated by IGF-1R depletion, potentially suppressing cell cycle-dependent processes required for HR. In contrast, IGF-1R depletion induced only minor radiosensitization in LNCaP cells, and did not influence repair. Cell cycle profiles were similar to DU145, so were unlikely to account for differences in repair responses.CONCLUSIONS:
These data indicate a role for IGF-1R in DSB repair, at least in part via HR, and support use of IGF-1R inhibitors with DNA damaging cancer treatments.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
Receptor IGF Tipo 1
/
Reparo do DNA
/
Quebras de DNA de Cadeia Dupla
Limite:
Humans
/
Male
Idioma:
En
Revista:
Radiother Oncol
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Reino Unido