Abstract 5514: Metformin sensitizes anticancer effect of dasatinib through AMPK-dependent ER stress in head and neck squamous cell carcinoma cells

Abstract

Abstract Purpose: Head and neck squamous cell carcinoma (HNSCC) is an important endemic disease in Taiwan with aggressive course and dismal outcome. Dasatinib is a Bcr-bl and Src kinase inhibitor that has potential against HNSCC. We recently disclosed that EGFR degradation is critical for dasatinib-induced apoptosis. Here, we further demonstrate that AMPK-dependent ER stress is responsible for this effect. Experimental design: Dasatinib-induced ER stress and AMPK activation was investigated in HNSCC cells including Ca9-22, HSC3, and SAS. The anti-cancer activity of dasatinib in combination with AMPK activator was examined in vitro and in vivo. EGFR expression and AMPK activation were correlated in human specimens. Results: Dasatinib-induced ER stress was involved in dasatinib-induced EGFR degradation and apoptosis, and ER stress mediated EGFR degradation in a c-cbl-dependent manner. In addition, dasatinib-induced AMPK activation led to dasatinib-induced ER stress and EGFR degradation, and activation of AMPK might be due to ATP decrease through the up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) induced by dasatinib. Furthermore, activation of AMPK by metformin potentiated dasatinib-induced anti-cancer effect in vitro and in vivo. The correlation of AMPK activation and EGFR expression was seen in HNSCC cells and human tumor specimens. Conclusions: Our results disclose that AMPK-dependent ER stress plays a crucial role in anti-cancer effect of dasatinib on HNSCC and activation of AMPK might enhance dasatinib efficacy. Note: This abstract was not presented at the meeting. Citation Format: Yu-Chin Lin, Meng-Hsuan Wu, Tzu-Tang Wei, Yun-Chieh Lin, Ching-Chow Chen. Metformin sensitizes anticancer effect of dasatinib through AMPK-dependent ER stress in head and neck squamous cell carcinoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5514. doi:10.1158/1538-7445.AM2014-5514