title: IKKβ regulates the repair of DNA double-strand breaks induced by ionizing radiation in MCF-7 breast cancer cells.
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.
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Lixian
authors.initials: L
authors.lastname: Wu
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.forename: Ningfei
authors.initials: N
authors.lastname: An
authors.forename: Junru
authors.initials: J
authors.lastname: Wang
authors.forename: Senthil
authors.initials: S
authors.lastname: Pazhanisamy
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011810:Quinoxalines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D011839:Radiation, Ionizing
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D007093:Imidazoles; D011810:Quinoxalines; D034741:RNA, Small Interfering; D051550:I-kappa B Kinase