Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Bcl-2-Like Protein 11
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Blotting, Western
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Cell Line, Tumor
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism
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Female
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Gefitinib
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Gene Expression Regulation, Neoplastic / drug effects
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HCT116 Cells
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Head and Neck Neoplasms / drug therapy*
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Head and Neck Neoplasms / metabolism
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Head and Neck Neoplasms / pathology
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Nude
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Quinazolines / pharmacology
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Tumor Protein p73
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Xenograft Model Antitumor Assays
Substances
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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DNA-Binding Proteins
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Membrane Proteins
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Nuclear Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Quinazolines
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TP73 protein, human
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Trp73 protein, mouse
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Tumor Protein p73
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Tumor Suppressor Proteins
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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Gefitinib