The double-stranded RNA-activated protein kinase mediates radiation resistance in mouse embryo fibroblasts through nuclear factor kappaB and Akt activation

von Holzen, Urs; Pataer, Abujiang; Raju, Uma; Bocangel, Dora; Vorburger, Stephan A; Liu, Yanna; Lu, Xiaolin; Roth, Jack A; Aggarwal, Bharat B; Barber, Glen N; Keyomarsi, Khandan; Hunt, Kelly K; Swisher, Stephen G (2007). The double-stranded RNA-activated protein kinase mediates radiation resistance in mouse embryo fibroblasts through nuclear factor kappaB and Akt activation. Clinical cancer research, 13(20), pp. 6032-9. Philadelphia, Pa.: American Association for Cancer Research 10.1158/1078-0432.CCR-06-2932

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PURPOSE: Activation of the double-stranded RNA-activated protein kinase (PKR) leads to the induction of various pathways including the down-regulation of translation through phosphorylation of the eukaryotic translation initiation factor 2alpha (eIF-2alpha). There have been no reports to date about the role of PKR in radiation sensitivity. EXPERIMENTAL DESIGN: A clonogenic survival assay was used to investigate the sensitivity of PKR mouse embryo fibroblasts (MEF) to radiation therapy. 2-Aminopurine (2-AP), a chemical inhibitor of PKR, was used to inhibit PKR activation. Nuclear factor-kappaB (NF-kappaB) activation was assessed by electrophoretic mobility shift assay (EMSA). Expression of PKR and downstream targets was examined by Western blot analysis and immunofluorescence. RESULTS: Ionizing radiation leads to dose- and time-dependent increases in PKR expression and function that contributes to increased cellular radiation resistance as shown by clonogenic survival and terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) apoptosis assays. Specific inhibition of PKR with the chemical inhibitor 2-AP restores radiation sensitivity. Plasmid transfection of the PKR wild-type (wt) gene into PKR(-/-) MEFs leads to increased radiation resistance. The protective effect of PKR to radiation may be mediated in part through NF-kappaB and Akt because both NF-kappaB and Akt are activated after ionizing radiation in PKR+/+ but not PKR-/- cells. CONCLUSIONS: We suggest a novel role for PKR as a mediator of radiation resistance modulated in part through the protective effects of NF-kappaB and Akt activation. The modification of PKR activity may be a novel strategy in the future to overcome radiation resistance.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
UniBE Contributor:	Vorburger, Stephan
ISSN:	1078-0432
ISBN:	17947465
Publisher:	American Association for Cancer Research
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:57
Last Modified:	05 Dec 2022 14:17
Publisher DOI:	10.1158/1078-0432.CCR-06-2932
PubMed ID:	17947465
Web of Science ID:	000250422700009
URI:	https://boris.unibe.ch/id/eprint/24252 (FactScience: 47808)