Degradation of epidermal growth factor receptor mediates dasatinib-induced apoptosis in head and neck squamous cell carcinoma cells.
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 down-regulation of EGFR and ERα. In conclusion, degradation of EGFR is a novel mechanism responsible for dasatinib-induced apoptosis in HNSCC cells.
Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.
Yu-Chin
YC
Lin
Meng-Hsuan
MH
Wu
Tzu-Tang
TT
Wei
Shu-Hui
SH
Chuang
Kuen-Feng
KF
Chen
Ann-Lii
AL
Cheng
Ching-Chow
CC
Chen
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000069439:Dasatinib