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NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699
The stress inducible transcription 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 transcripti...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191117/ https://www.ncbi.nlm.nih.gov/pubmed/21706052 http://dx.doi.org/10.1038/onc.2011.229 |
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author | Hunter, Jill E. Willmore, Elaine Irving, Julie A. E. Hostomsky, Zdenek Veuger, Stephany J. Durkacz, Barbara W. |
author_facet | Hunter, Jill E. Willmore, Elaine Irving, Julie A. E. Hostomsky, Zdenek Veuger, Stephany J. Durkacz, Barbara W. |
author_sort | Hunter, Jill E. |
collection | PubMed |
description | The stress inducible transcription 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 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. Since 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 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. |
format | Online Article Text |
id | pubmed-3191117 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
record_format | MEDLINE/PubMed |
spelling | pubmed-31911172012-07-12 NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699 Hunter, Jill E. Willmore, Elaine Irving, Julie A. E. Hostomsky, Zdenek Veuger, Stephany J. Durkacz, Barbara W. Oncogene Article The stress inducible transcription 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 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. Since 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 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. 2011-06-27 2012-01-12 /pmc/articles/PMC3191117/ /pubmed/21706052 http://dx.doi.org/10.1038/onc.2011.229 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Hunter, Jill E. Willmore, Elaine Irving, Julie A. E. Hostomsky, Zdenek Veuger, Stephany J. Durkacz, Barbara W. NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699 |
title | NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699 |
title_full | NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699 |
title_fullStr | NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699 |
title_full_unstemmed | NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699 |
title_short | NF-κB mediates radio-sensitization by the PARP-1 inhibitor, AG-014699 |
title_sort | nf-κb mediates radio-sensitization by the parp-1 inhibitor, ag-014699 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191117/ https://www.ncbi.nlm.nih.gov/pubmed/21706052 http://dx.doi.org/10.1038/onc.2011.229 |
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