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

// Yu-Chin Lin 1,2,3 , Meng-Hsuan Wu 1,* , Tzu-Tang Wei 1,* , Yun-Chieh Lin 1,* , Wen-Chih Huang 4 , Liang-Yu Huang 1 , Yi-Ting Lin 1 , and Ching-Chow Chen 1 1 Graduate Institute of Pharmacology, National Taiwan University College of Medicine; 2 Department of Oncology, National Taiwan University Hospital; 3 Department of Internal Medicine and 4 Department of Pathology, Far-Eastern Memorial Hospital; * Equal contribution to work Correspondence: Ching-Chow Chen, email: // Keywords : AMPK, ER stress, EGFR, dasatinib, PDK4 Received : November 26, 2013 Accepted : January 7, 2014 Published : January 7, 2014 Abstract 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 event. Dasatinib induced ER stress which mediated EGFR degradation in a c-cbl-dependent manner. AMPK activation induced by dasatinib might be due to ATP decrease through the up-regulation of pyruvate dehydrogenase kinase 4 (PDK4). Furthermore, activation of AMPK by metformin sensitized dasatinib-induced in vitro and in vivo anti-cancer effect. The correlation of AMPK activation and EGFR expression was seen in HNSCC cells and human tumor specimens. Our results disclose that AMPK-dependent ER stress plays a crucial role in the anti-cancer effect of dasatinib in HNSCC and further activation of AMPK by metformin might enhance dasatinib efficacy.