IKK? regulates the repair of DNA double-strand breaks induced by ionizing radiation in MCF-7 breast cancer cells.

ABSTRACT: Activation of the IKK-NF?B 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 NF?B. 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-NF?B pathway also regulates DSB repair to promote cell survival after IR. We found that inhibition of the IKK-NF?B pathway with a specific IKK? inhibitor significantly reduced the repair of IR-induced DSBs in MCF-7 cells. The repair of DSBs was also significantly inhibited by silencing IKK? expression with IKK? shRNA. However, down-regulation of IKK? expression with IKK? shRNA had no significant effect on the repair of IR-induced DSBs. Similar findings were also observed in IKK? and/or IKK? knockout mouse embryonic fibroblasts (MEFs). More importantly, inhibition of IKK? with an inhibitor or down-regulation of IKK? with IKK? shRNA sensitized MCF-7 cells to IR-induced clonogenic cell death. DSB repair function and resistance to IR were completely restored by IKK? reconstitution in IKK?-knockdown MCF-7 cells. These findings demonstrate that IKK? can regulate the repair of DSBs, a previously undescribed and important IKK? kinase function; and inhibition of DSB repair may contribute to cance cell radiosensitization induced by IKK? inhibition. As such, specific inhibition of IKK? may represents a more effective approach to sensitize cancer cells to radiotherapy.

SUBMITTER: Wu L 

PROVIDER: S-EPMC3072401 | biostudies-other | 2011 Apr

REPOSITORIES: biostudies-other