Sensitization by Radio-Chemotherapy in Targeting Therapy for Survival Signal Transduction Pathways against Head and Neck Cancers

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NBS1 is essential for the repair of DNA double-strand breaks (DSBs) and may play a important role in the homologous recombination repair and nonhomologous end joining repair. In this study, we examined whether suppressed NBS1 expression by small interference RNA (siRNA) could enhance radiation sensitivity in cancer cells with different TP53 status. We used human tongue cancer cells differing in TP53 gene status (SAS/neo bearing wild-type TP53 or SAS/mp53 bearing mutant TP53). A DNA cassette expressing siRNA targeted for the NBS1 gene was transfected into those cell lines. Cellular levels of NBS1 and other proteins were analyzed using Western blotting. We found that the radiation sensitivity of SAS/neo and SAS/mp53 was enhanced by transfection of the DNA cassette. In the NBS1-siRNA-transfected cells, we observed decreased constitutive expression of NBS1 protein and decreased radiation-induced accumulation of phosphorylated NBS1 protein. In addition, radiation-induced expression of the transcription factor NF-kB was suppressed by NBS1-siRNA. Enhanced X-ray sensitivity after NBS1-siRNA transfection was achieved in TP53 wild-type cells and sensitivity was even more pronounced in TP53 mutant cells. Our data suggest that the sensitization to radiation results from NBS1-siRNA-mediated suppression of DNA repair and/ or X-ray-induced cell survival signaling pathways through NF-kB. siRNA targeting appears to be a novel radiation-sensitizing agent, particularly in human TP53 mutant cancer cells.