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NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699

Oncogene volume 31, pages 251–264 (2012)Cite this article

A Correction to this article was published on 09 December 2022

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Abstract

The stress-inducible transcription factor, nuclear factor (NF)-κB induces genes involved in proliferation and apoptosis. Aberrant NF-κB activity is common in cancer and contributes to therapeutic-resistance. Poly(ADP-ribose) polymerase-1 (PARP-1) is activated during DNA strand break repair and is a known transcriptional co-regulator. Here, we investigated the role of PARP-1 function during NF-κB activation using p65 small interfering RNA (siRNA), PARP siRNA or the potent PARP-1 inhibitor, AG-014699. Survival and apoptosis assays showed that NF-κB p65−/− cells were more sensitive to ionizing radiation (IR) than p65+/+ cells. Co-incubation with p65 siRNA, PARP siRNA or AG-014699 radio-sensitized p65+/+, but not p65−/− cells, demonstrating that PARP-1 mediates its effects on survival via NF-κB. Single-strand break (SSB) repair kinetics, and the effect SSB repair inhibition by AG-014699 were similar in p65+/+ and p65−/− cells. As preventing SSB repair did not radio-sensitize p65−/− cells, we conclude that radio-sensitization by AG-014699 is due to downstream inhibition of NF-κB activation, and independent of SSB repair inhibition. PARP-1 catalytic activity was essential for IR-induced p65 DNA binding and NF-κB-dependent gene transcription, whereas for tumor necrosis factor (TNF)-α-treated cells, PARP-1 protein alone was sufficient. We hypothesize that this stimulus-dependent differential is mediated via stimulation of the poly(ADP-ribose) polymer, which was induced following IR, not TNF-α. Targeting DNA damage-activated NF-κB using AG-014699 may therefore overcome toxicity observed with classical NF-κB inhibitors without compromising other vital inflammatory functions. These data highlight the potential of PARP-1 inhibitors to overcome NF-κB-mediated therapeutic resistance and widens the spectrum of cancers in which these agents may be utilized.

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Acknowledgements

We gratefully acknowledge Pfizer for the supply of AG-014699. This work was supported by Cancer Research UK, grant number C7369/A8048.

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Author notes

  1. S J Veuger and B W Durkacz: These authors contributed equally to this work.

Authors and Affiliations

  1. Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Tyneside, UK

    J E Hunter, E Willmore, J A E Irving, S J Veuger & B W Durkacz

  2. Pfizer GRD, La Jolla, CA, USA

    Z Hostomsky

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  1. J E Hunter
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Correspondence to S J Veuger.

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Hunter, J., Willmore, E., Irving, J. et al. NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699. Oncogene 31, 251–264 (2012). https://doi.org/10.1038/onc.2011.229

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