PUMA mediates EGFR tyrosine kinase inhibitor-induced apoptosis in head and neck cancer cells

• Published in: Oncogene Vol. 28; no. 24; pp. 2348 - 2357
• Main Authors: SUN, Q, MING, L, THOMAS, S. M, WANG, Y, CHEN, Z. G, FERRIS, R. L, GRANDIS, J. R, ZHANG, L, YU, J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 18.06.2009
• Subjects: 1-Phosphatidylinositol 3-kinase; Ageing, cell death; AKT protein; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2 protein; Bcl-2-Like Protein 11; Biological and medical sciences; Blotting, Western; Cancer cells; Care and treatment; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemotherapy; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; Female; Fundamental and applied biological sciences. Psychology; Gefitinib; Gene Expression Regulation, Neoplastic - drug effects; HCT116 Cells; Head & neck cancer; Head and neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; Kinases; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Nude; Molecular and cellular biology; Molecular biology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; p53 Protein; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal transduction; Signal Transduction - drug effects; Solid tumors; Squamous cell carcinoma; Transcription; Tumor Protein p73; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Tyrosine kinase inhibitors; Xenograft Model Antitumor Assays; United States; Enzyme; Transferases; Akt protein kinase; Malignant tumor; EGFR-TKI; Carcinogenesis; p73; PI3K/AKT; ENT disease; Head and neck cancer; Inhibitor; PUMA; Protein-tyrosine kinase; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.108

Overexpression of epidermal growth factor receptor (EGFR) is found in over 80% of head and neck squamous cell carcinomas (HNSCC) and associated with poor clinical outcomes. EFGR selective tyrosine kinase inhibitors (TKIs) or antibodies have recently emerged as promising treatments for solid tumors, including HNSCC, though the response rate to these agents is low. p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, is required for apoptosis induced by p53 and various chemotherapeutic agents. In this study, we show that PUMA induction is correlated with EGFR-TKI sensitivity, and is mediated through the p53 family protein p73beta and inhibition of the PI3K/AKT pathway. In some HNSCC cells, the gefitinib-induced degradation of oncogenic Delta Np63 seems to facilitate p73-mediated PUMA transcription. Inhibiting PUMA expression by small hairpin RNA (shRNA) impairs gefitinib-induced apoptosis. Furthermore, PUMA or BH3 mimetics sensitize HNSCC cells to gefitinib-induced apoptosis. Our results suggest that PUMA induction through p73 represents a new mechanism of EGFR inhibitor-induced apoptosis, and provide potential ways for enhancing and predicting the sensitivity to EGFR-targeted therapies in HNSCC.