PMID:21490922

Citation	Wu, L, Shao, L, An, N, Wang, J, Pazhanisamy, S, Feng, W, Hauer-Jensen, M, Miyamoto, S and Zhou, D (2011) IKKβ regulates the repair of DNA double-strand breaks induced by ionizing radiation in MCF-7 breast cancer cells. PLoS ONE 6:e18447
Abstract	Activation of the IKK-NFκB pathway increases the resistance of cancer cells to ionizing radiation (IR). This effect has been largely attributed to the induction of anti-apoptotic proteins by NFκB. Since efficient repair of DNA double strand breaks (DSBs) is required for the clonogenic survival of irradiated cells, we investigated if activation of the IKK-NFκB pathway also regulates DSB repair to promote cell survival after IR. We found that inhibition of the IKK-NFκB pathway with a specific IKKβ inhibitor significantly reduced the repair of IR-induced DSBs in MCF-7 cells. The repair of DSBs was also significantly inhibited by silencing IKKβ expression with IKKβ shRNA. However, down-regulation of IKKα expression with IKKα shRNA had no significant effect on the repair of IR-induced DSBs. Similar findings were also observed in IKKα and/or IKKβ knockout mouse embryonic fibroblasts (MEFs). More importantly, inhibition of IKKβ with an inhibitor or down-regulation of IKKβ with IKKβ shRNA sensitized MCF-7 cells to IR-induced clonogenic cell death. DSB repair function and resistance to IR were completely restored by IKKβ reconstitution in IKKβ-knockdown MCF-7 cells. These findings demonstrate that IKKβ can regulate the repair of DSBs, a previously undescribed and important IKKβ kinase function; and inhibition of DSB repair may contribute to cance cell radiosensitization induced by IKKβ inhibition. As such, specific inhibition of IKKβ may represents a more effective approach to sensitize cancer cells to radiotherapy.
Links	PubMed PMC3072401 Online version:10.1371/journal.pone.0018447
Keywords	Animals; Blotting, Western; Cell Line, Tumor; Cells, Cultured; DNA Breaks, Double-Stranded/radiation effects; DNA Repair/genetics; DNA Repair/physiology; Fibroblasts/drug effects; Fibroblasts/metabolism; Humans; I-kappa B Kinase/antagonists & inhibitors; I-kappa B Kinase/genetics; I-kappa B Kinase/metabolism; Imidazoles/pharmacology; Mice; Mice, Knockout; Polymerase Chain Reaction; Quinoxalines/pharmacology; RNA, Small Interfering/genetics; Radiation, Ionizing
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:IKKB		GO:0006302: double-strand break repair	ECO:0000315:		P		Fig 4D,F. IKKβ knockdown cells exhibited a significant reduction in the repair of IR-induced DSBs. Fig 5. The DSB repair function was completely restored in MCF-7/IKKbeta(-) after transfection with either WT-IKKβ or SSEE-IKKβ compared to MCF-7 cells.	complete

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