Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress.
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.
Yu-Chin
YC
Lin
Meng-Hsuan
MH
Wu
Tzu-Tang
TT
Wei
Yun-Chieh
YC
Lin
Wen-Chih
WC
Huang
Liang-Yu
LY
Huang
Yi-Ting
YT
Lin
Ching-Chow
CC
Chen
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D011743:Pyrimidines; D013844:Thiazoles; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D000069439:Dasatinib