EMAIL THIS PAGE TO A FRIEND

Oncogene

IGF-1R inhibition enhances radiosensitivity and delays double-strand break repair by both non-homologous end-joining and homologous recombination.


PMID 24186206

Abstract

Inhibition of type 1 insulin-like growth factor receptor (IGF-1R) enhances tumor cell sensitivity to ionizing radiation. It is not clear how this effect is mediated, nor whether this approach can be applied effectively in the clinic. We previously showed that IGF-1R depletion delays repair of radiation-induced DNA double-strand breaks (DSBs), unlikely to be explained entirely by reduction in homologous recombination (HR) repair. The current study tested the hypothesis that IGF-1R inhibition induces a repair defect that involves non-homologous end joining (NHEJ). IGF-1R inhibitor AZ12253801 blocked cell survival and radiosensitized IGF-1R-overexpressing murine fibroblasts but not isogenic IGF-1R-null cells, supporting specificity for IGF-1R. IGF-1R inhibition enhanced radiosensitivity in DU145, PC3 and 22Rv1 prostate cancer cells, comparable to effects of Ataxia Telangiectasia Mutated inhibition. AZ12253801-treated DU145 cells showed delayed resolution of γH2AX foci, apparent within 1 h of irradiation and persisting for 24 h. In contrast, IGF-1R inhibition did not influence radiosensitivity or γH2AX focus resolution in LNCaP-LN3 cells, suggesting that radiosensitization tracks with the ability of IGF-1R to influence DSB repair. To differentiate effects on repair from growth and cell-survival responses, we tested AZ12253801 in DU145 cells at sub-SF50 concentrations that had no early (⩽48 h) effects on cell cycle distribution or apoptosis induction. Irradiated cultures contained abnormal mitoses, and after 5 days IGF-1R-inhibited cells showed enhanced radiation-induced polyploidy and nuclear fragmentation, consistent with the consequences of entry into mitosis with incompletely repaired DNA. AZ12253801 radiosensitized DNA-dependent protein kinase (DNA-PK)-proficient but not DNA-PK-deficient glioblastoma cells, and did not radiosensitize DNA-PK-inhibited DU145 cells, suggesting that in the context of DSB repair, IGF-1R functions in the same pathway as DNA-PK. Finally, IGF-1R inhibition attenuated repair by both NHEJ and HR in HEK293 reporter assays. These data indicate that IGF-1R influences DSB repair by both major DSB repair pathways, findings that may inform clinical application of this approach.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

GW21062 Anti-CD221 antibody produced in chicken, affinity isolated antibody, buffered aqueous solution
SAB4500348
Anti-Histone H3 (Acetyl-Lys14) antibody produced in rabbit, affinity isolated antibody
SAB4500349
Anti-Histone H3 (Acetyl-Lys18) antibody produced in rabbit, affinity isolated antibody
SAB4500350
Anti-Histone H3 (Acetyl-Lys23) antibody produced in rabbit, affinity isolated antibody
SAB4500351
Anti-Histone H3 (Acetyl-Lys27) antibody produced in rabbit, affinity isolated antibody
SAB4500347
Anti-Histone H3 (Acetyl-Lys9) antibody produced in rabbit, affinity isolated antibody
H9289
Anti-Histone H3 (N-terminal) antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
H0164
Anti-Histone H3 antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
SAB4300359
Anti-IGF1R (Ab-1161) antibody produced in rabbit, affinity isolated antibody
SAB4300360
Anti-IGF1R (Ab-1165/1166) antibody produced in rabbit, affinity isolated antibody
SAB4300548
Anti-IGF1R (Ab-1280) antibody produced in rabbit, affinity isolated antibody
SAB4300549
Anti-IGF1R (Ab-1346) antibody produced in rabbit, affinity isolated antibody
SAB2101136
Anti-IGF1R antibody produced in rabbit, affinity isolated antibody
SAB5300081
Monoclonal Anti-IGF1R antibody produced in mouse, clone 3C8B1, ascites fluid
SAB5300082
Monoclonal Anti-IGF1R antibody produced in mouse, clone 3G5C1, ascites fluid
PLA0148
Rabbit anti-Histone H3 Antibody, Affinity Purified, Powered by Bethyl Laboratories, Inc.