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.
Highlights
Endoplasmic reticulum (ER) is the primary site for protein synthesis, folding, and trafficking
We recently find that dasatinib-induced Epidermal growth factor receptor (EGFR) degradation occurs in sensitive but not resistant cells, and c-cbl-dependent lysosome pathway is responsible for this effect [20]
We found that dasatinib induced eIF2α phosphorylation and CHOP expression in sensitive Ca9-22 and HSC3 cells (IC50 0.45uM and 0.78uM, respectively) but not resistant SAS cells (IC50 > 10uM), indicating that dasatinib inducted ER stress in sensitive cells. 4-phenyl butyric acid (PBA), an ER stress inhibitor, attenuated dasatinibinduced EGFR degradation and apoptosis
Summary
Endoplasmic reticulum (ER) is the primary site for protein synthesis, folding, and trafficking. Metabolic stress impairs protein processing capacity to accumulate nascent proteins leading to ER stress [1]. If ER stress is persistent and unresolved, UPR will switch pro-survival signaling to proapoptotic to remove damaged cells [2]. The UPR is regulated by three ER intermembrane transducers: PKR-like ER kinase (PERK), inositol requiring 1 (IRE1), and activating transcription factor 6 (ATF6) [1]. PERK phosphorylates initiation factor 2α (eIF2α) to attenuate protein synthesis, and eIF2α can regulate CHOP expression to mediate apoptosis [3]. ER stress resulted from rapid proliferation-induced nutrient deficiency and hypoxia in cancer cells is compensated by pro-survival UPR [4]. ER stress might be a target for cancer treatment
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