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Ionizing radiation-induced NF-κB activation requires PARP-1 function to confer radioresistance

Oncogene volume 28, pages 832–842 (2009)Cite this article

A Correction to this article was published on 26 January 2023

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Abstract

Recent reports implicate poly(ADP-ribose) polymerase-1 (PARP-1) in the activation of nuclear factor kappaB (NF-κB). We investigated the role of PARP-1 in the NF-κB signalling cascade induced by ionizing radiation (IR). AG14361, a potent PARP-1 inhibitor, was used in two breast cancer cell lines expressing different levels of constitutively activated NF-κB, as well as mouse embryonic fibroblasts (MEFs) proficient or deficient for PARP-1 or NF-κB p65. In the breast cancer cell lines, AG14361 had no effect on IR-induced degradation of IκBα or nuclear translocation of p50 or p65. However, AG14361 inhibited IR-induced NF-κB-dependent transcription of a luciferase reporter gene. Similarly, in PARP-1−/− MEFs, IR-induced nuclear translocation of p50 and p65 was normal, but κB binding and transcriptional activation did not occur. AG14361 sensitized both breast cancer cell lines to IR-induced cell killing, inhibited IR-induced XIAP expression and increased caspase-3 activity. However, AG14361 failed to increase IR-induced caspase activity when p65 was knocked down by siRNA. Consistent with this, AG14361 sensitized p65+/+ but not p65−/− MEFs to IR. We conclude that PARP-1 activity is essential in the upstream regulation of IR-induced NF-κB activation. These data indicate that potentiation of IR-induced cytotoxicity by AG14361 is mediated solely by inhibition of NF-κB activation.

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Acknowledgements

This work was supported by the Breast Cancer Campaign, UK and Cancer Research UK.

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  1. Northern Institute for Cancer Research, Medical School, University of Newcastle, Newcastle upon Tyne, Tyne and Wear, UK

    S J Veuger, J E Hunter & B W Durkacz

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  1. S J Veuger
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Correspondence to B W Durkacz.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Veuger, S., Hunter, J. & Durkacz, B. Ionizing radiation-induced NF-κB activation requires PARP-1 function to confer radioresistance. Oncogene 28, 832–842 (2009). https://doi.org/10.1038/onc.2008.439

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