Degradation of epidermal growth factor receptor mediates dasatinib-induced apoptosis in head and neck squamous cell carcinoma cells
Journal
Neoplasia (United States)
Journal Volume
14
Journal Issue
6
Pages
463-475
Date Issued
2012
Author(s)
Abstract
Epidermal growth factor receptor (EGFR) is an important oncoprotein that promotes cell growth and proliferation. Dasatinib, a bcr-abl inhibitor, has been approved clinically for the treatment of chronic myeloid leukemia and demonstrated to be effective against solid tumors in vitro through Src inhibition. Here, we disclose that EGFR degradation mediated dasatinib-induced apoptosis in head and neck squamous cell carcinoma (HNSCC) cells. HNSCC cells, including Ca9-22, FaDu, HSC3, SAS, SCC-25, and UMSCC1, were treated with dasatinib, and cell viability, apoptosis, and underlying signal transduction were evaluated. Dasatinib exhibited differential sensitivities against HNSCC cells. Growth inhibition and apoptosis were correlated with its inhibition on Akt, Erk, and Bcl-2, irrespective of Src inhibition. Accordingly, we found that down-regulation of EGFR was a determinant of dasatinib sensitivity. Lysosome inhibitor reversed dasatinib-induced EGFR down-regulation, and c-cbl activity was increased by dasatinib, indicating that dasatinib-induced EGFR down-regulation might be through c-cbl-mediated lysosome degradation. Increased EGFR activation by ligand administration rescued cells from dasatinib-induced apoptosis, whereas inhibition of EGFR enhanced its apoptotic effect. Estrogen receptor α (ERα) was demonstrated to play a role in Bcl-2 expression, and dasatinib inhibited ERα at the pretranslational level. ERα was associated with EGFR in dasatinib-treated HNSCC cells. Furthermore, the xenograft model showed that dasatinib inhibited HSC3 tumor growth through in vivo downregulation of EGFR and ERα. In conclusion, degradation of EGFR is a novel mechanism responsible for dasatinibinduced apoptosis in HNSCC cells. ? 2012 Neoplasia Press, Inc. All rights reserved.
SDGs
Other Subjects
Cbl protein; dasatinib; epidermal growth factor receptor; estrogen receptor alpha; lysosome associated membrane protein 1; mitogen activated protein kinase; procaspase 3; protein Bak; protein Bax; protein bcl 2; protein bcl xl; protein kinase B; protein mcl 1; protein tyrosine kinase; animal experiment; animal model; apoptosis; article; cancer inhibition; cell viability; confocal microscopy; controlled study; down regulation; drug sensitivity; flow cytometry; head and neck squamous cell carcinoma; human; human cell; immunofluorescence test; lysosome; male; mouse; nonhuman; priority journal; protein degradation; protein expression; real time polymerase chain reaction; signal transduction; Western blotting
Publisher
Elsevier B.V.
Type
journal article