Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress
Journal
Oncotarget
Journal Volume
5
Journal Issue
1
Pages
298-308
Date Issued
2014
Author(s)
Abstract
Head and neck squamous cell carcinoma (HNSCC) is an important endemic disease in Taiwan with aggressive course and dismal outcome. Dasatinib is a Bcrbl 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.
SDGs
Other Subjects
adenosine triphosphate; Cbl protein; dasatinib; epidermal growth factor receptor; glucose; hydroxymethylglutaryl coenzyme A reductase kinase; metformin; pyruvate dehydrogenase kinase 4; antineoplastic agent; dasatinib; hydroxymethylglutaryl coenzyme A reductase kinase; metformin; pyrimidine derivative; thiazole derivative; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer inhibition; controlled study; drug potentiation; endoplasmic reticulum stress; female; head and neck squamous cell carcinoma; human; human tissue; mouse; nonhuman; protein degradation; upregulation; animal; Carcinoma, Squamous Cell; cell growth; drug effects; drug screening; endoplasmic reticulum stress; enzymology; Head and Neck Neoplasms; metabolism; nude mouse; pathology; physiology; tumor cell line; AMP-Activated Protein Kinases; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Squamous Cell; Cell Growth Processes; Cell Line, Tumor; Drug Synergism; Endoplasmic Reticulum Stress; Female; Head and Neck Neoplasms; Humans; Metformin; Mice; Mice, Nude; Pyrimidines; Thiazoles; Xenograft Model Antitumor Assays
Type
journal article