Background: A major challenge affecting outcomes of patients with squamous cell carcinomas of the head and neck (SCCHN) is radiation resistance. Overexpression of survivin is associated with radiation resistance and poor survival. Our study objectives were to: 1) evaluate the effects of survivin expression level on radiosensitivity in SCCHN cell lines; 2) identify the effect of survivin on DNA damage repair following radiation exposure in SCCHN cells; 3) evaluate the feasibility and efficacy of the combination therapy of survivin inhibitor YM155 and radiation in SCCHN. Methods: SCCHN cell lines, including JHU-022, PCI-15A and Tu686 were used to evaluate the role of survivin in DNA double strand break (DSB) repair following radiation exposure. To determine whether survivin specifically targets the sites of DNA damage, we performed ChIP assays using PCI-15A cells carrying the DR-GFP homologous recombination reporter. The in vitro effects of YM155 on sensitizing resistant cells to radiation were also evaluated using these cell lines. Results: The fraction surviving radiation was about 2.5-fold greater in PCI-15A and Tu686 cells compared with that in JHU-022 cells. As expected, survivin protein levels were elevated in PCI-15A and Tu686 cells compared with JHU-022 cells, suggesting an inverse correlation between survivin expression and radiosensitivity. Clonogenic survival following radiation exposure was inhibited by depletion of survivin in PCI-15A cells by siRNA, and increased by overexpression of survivin in JHU-022 cells. Inhibition of survivin by YM155 enhances the efficacy of radiation in PCI-15A cells. Immunoblotting revealed that radiation induced nuclear accumulation of survivin and its complex with γ-H2X, and DNA-PKCs in PCI-15A cells, suggesting survivin was involved in DNA damage response and repair induced by radiation. ChIP assay further confirmed that survivin specifically targeted and bound to the DNA DSB site, which is consistent with results obtained from immunofluorescence analysis. Conclusions: Survivin is involved in DNA damage response and repair induced by radiation exposure in SCCHN cells. Inhibition of survivin by YM155 enhances the efficacy of radiation, and may provide a novel therapeutic approach to improve the efficacy of radiotherapy in SCCHN. (This research was supported by the National Cancer Institute award P50 CA128613, and GCC Distinguished Cancer Scholar to Dong M. Shin, Zhuo (Georgia) Chen, and Jonathan J Beitler)
Citation Format: Xu Wang, Jonathan J. Beitler, Wen Huang, Guo Chen, Sreenivas Nannapaneni, Nabil F. Saba, Xingming Deng, Zhuo G. Chen, Dong M. Shin. Survivin contributes to radiation resistance in head and neck cancer through regulation of DNA damage repair. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 515.