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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.

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