Abstract 2626: Phospho-Akt is the molecular determinant of bortezomib sensitivity to head and neck squamous cells

Abstract

Abstract Introduction: Head and neck squamous cell carcinoma (HNSCC) is a worldwide prevalent cancer with aggressive clinical courses and dismal outcomes. Incorporation of cetuximab, an antibody against epidermal growth factor receptor, had led to advance of treatment, but the efficacy is modest. Therefore, new treatment for HNSCC is needed. Bortezomib, a proteasome inhibitor approved for treatment of myeloma and lymphoma, demonstrated activities for various solid tumors. Here, we report the differential sensitivity of bortezomib for HNSCC cells and identify the major molecular determinant responsible for activity. Material and method: HNSCC cells, including Ca9-22, SAS, SCC-25 and FaDu, were treated with bortezomib and evaluated for viability, apoptosis, and signal transduction. MTT assay was used for viability. Flow cytometry and Western blotting were performed for apoptosis and signal transduction analysis. Gene silencing was done by small interference RNA (siRNA). Results: Four HNSCC cells showed differential sensitivities to bortezomib. Thorough comparison of molecular change before and after treatment of bortezomib, we found that Akt played a significant role in mediating bortezomib sensitivity to HNSCC cells. Our data demonstrated that bortezomib down-regulated phospho-Akt (Ser473) in dose- and time-dependent manner, and significantly correlated with apoptosis. Knocking down Akt1 by small interference RNA enhanced sensitivity of bortezomib whereas ectopic expression of Akt conferred resistance to bortezomib, suggesting that Akt is indispensible in mediating bortezomib's effect on HNSCC cells. Conclusion: Down-regulation of phospho-Akt represents a molecular determinant of bortezomib-induced apoptosis in HNSCC cells and may be a biomarker for predicting clinical response to HNSCC treatment. Targeting Akt signaling enhances sensitivity to bortezomib in HNSCC cells, which might provide a new approach for the combinational therapy of HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2626.