Abstract 1298: The role of nuclear factor kappa B in survival of human papillomavirus-positive head and neck cancer cell lines.

Abstract

Abstract Nuclear factor kappa B (NFκB) has been implicated in the development of head and neck squamous cell carcinoma (HNSCC) from premalignant changes to tumor progression, and in treatment resistance and recurrence. However, the roles of NFκB in the sensitivity to chemoradiation of human papillomavirus (HPV)-associated HNSCC have not been well defined. Previously we reported that high expression of NFκB detected by immunohistochemistry in pretreated HPV+ oropharyngeal cancer patients was significantly associated with poor progression free survival (AACR 2012 Abstract #4489). Therefore, we hypothesized that NFκB could play a role in pro-survival in HPV+ head and neck cancer cells. We first examined the sensitivity of five HPV+ head and neck cancer cell lines (HPV16: UDSCC2, 93-VU-147T, UM-SCC47, UPCI:SCC90, HPV18: SCC1483) to radiation and cisplatin, Consistent with current models, when we knocked down expression of the HPV16E6 oncogene, SCC47 and SCC1483 cells with restored expression of p53 displayed a significant reduction in S phase entry as revealed by cell cycle analysis (SCC47: scrambled control 14.08% ± 0.55% versus siRNA-E6 6.39% ± 2.40, p=0.004; SCC1483: scrambled control 13.39% ± 1.28% versus 7.49% ± 0.83, p=0.002). In addition, all five cell lines displayed reduced sensitivity to cisplatin compared with cells treated with scrambled control siRNA. The basal level of activated NFκB in HPV+ cell lines was correlated with the sensitivity to radiation and cisplatin as assessed by colony formation and cell growth assays. Suppression of NFκBp65 by siRNA resulted in marked increases in apoptosis associated with reduction of Bcl-2 in both SCC47 and SCC1483 cells. This pattern was more pronounced with increasing doses of the proteasome inhibitor bortezomib (32.5 to 130 nM for 48 to 72 hr). Furthermore, SCC47 and SCC1483 cells treated with siRNA NFκBp65 displayed a significantly greater level of apoptosis induced by radiation or cisplatin compared to cells treated with non-targeted control siRNA, indicating a pro-survival effect for NFκB. Further studies are warranted to delineate the effects of HPV oncogene interactions with NFκB signaling pathways on chemoradiation sensitivity. (This study was supported by the V Foundation). Citation Format: Hongzheng Zhang, Zhongliang Hu, Ning Jiang, Rossella Marullo, Paul W. Doetsch, William D. Hunt, Georgia Z. Chen, Dong M. Shin. The role of nuclear factor kappa B in survival of human papillomavirus-positive head and neck cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1298. doi:10.1158/1538-7445.AM2013-1298