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Ionizing radiation-induced NF-kappaB activation requires PARP-1 function to confer radioresistance
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Dr Stephany Veuger
Emeritus Professor Barbara Durkacz
Veuger SJ, Hunter JE, Durkacz BW
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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.
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