About Open Access
Ionizing radiation-induced NF-kappaB activation requires PARP-1 function to confer radioresistance
Lookup NU author(s)
Dr Stephany Veuger
Emeritus Professor Barbara Durkacz
Veuger SJ, Hunter JE, Durkacz BW
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
Recent reports implicate poly(ADP-ribose) polymerase-1 (PARP-1) in the activation of nuclear factor kappaB (NF-B). We investigated the role of PARP-1 in the NF-B 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-B, as well as mouse embryonic fibroblasts (MEFs) proficient or deficient for PARP-1 or NF-B p65. In the breast cancer cell lines, AG14361 had no effect on IR-induced degradation of IB or nuclear translocation of p50 or p65. However, AG14361 inhibited IR-induced NF-B-dependent transcription of a luciferase reporter gene. Similarly, in PARP-1
MEFs, IR-induced nuclear translocation of p50 and p65 was normal, but B 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-B activation. These data indicate that potentiation of IR-induced cytotoxicity by AG14361 is mediated solely by inhibition of NF-B activation.
Nature Publishing Group
Altmetrics provided by
Newcastle University Library, NE2 4HQ, United Kingdom. Tel: 0044 (191) 222 7657
©2016 Newcastle University Library