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

Abstract

Recent reports implicate poly(ADP-ribose) polymerase-1 (PARP-1) in the activation of nuclear factor kappaB (NF-kappaB). We investigated the role of PARP-1 in the NF-kappaB 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-kappaB, as well as mouse embryonic fibroblasts (MEFs) proficient or deficient for PARP-1 or NF-kappaB p65. In the breast cancer cell lines, AG14361 had no effect on IR-induced degradation of IkappaBalpha or nuclear translocation of p50 or p65. However, AG14361 inhibited IR-induced NF-kappaB-dependent transcription of a luciferase reporter gene. Similarly, in PARP-1(-/-) MEFs, IR-induced nuclear translocation of p50 and p65 was normal, but kappaB 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-kappaB activation. These data indicate that potentiation of IR-induced cytotoxicity by AG14361 is mediated solely by inhibition of NF-kappaB activation.

• Authors: S J Veuger, J E Hunter, B W Durkacz
• Journal: Oncogene (Oncogene) Vol. 28 Issue 6 Pg. 832-42 (Feb 12 2009) ISSN: 1476-5594 [Electronic] England
• PMID: 19060926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(4-dimethylaminomethylphenyl)-8,9-dihydro-7H-2,7,9a-benzo(cd)azulen-6-one
• Azulenes
• Enzyme Inhibitors
• NF-kappa B
• Poly(ADP-ribose) Polymerase Inhibitors
• RELA protein, human
• RNA, Small Interfering
• Transcription Factor RelA
• Benzodiazepines
• Poly(ADP-ribose) Polymerases
• Caspases

Topics

• Active Transport, Cell Nucleus
• Apoptosis
• Azulenes (pharmacology)
• Benzodiazepines (pharmacology)
• Breast Neoplasms (metabolism)
• Caspases (metabolism)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic (radiation effects)
• Humans
• Models, Biological
• NF-kappa B (metabolism)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• RNA, Small Interfering (metabolism)
• Radiation, Ionizing
• Transcription Factor RelA (metabolism)