Inhibition of epidermal growth factor receptor signaling decreases p63 expression in head and neck squamous carcinoma cells.

Matheny KE, Barbieri CE, Sniezek JC, Arteaga CL, Pietenpol JA
Laryngoscope. 2003 113 (6): 936-9

PMID: 12782800 · DOI:10.1097/00005537-200306000-00004

OBJECTIVES/HYPOTHESIS - Both the epidermal growth factor receptor (EGFR) and the p53 homologue p63 are overexpressed in a significant number of cases of head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor and p63 both possess oncogenic properties, including the potential to increase cell proliferation and antagonize apoptosis. ZD1839 ("Iressa") is an adenosine triphosphate-competitive inhibitor specific to the EGFR tyrosine kinase currently under evaluation as a chemotherapeutic agent in HNSCC. The objective was to investigate whether p63 expression is decreased after treatment of HNSCC cells with ZD1839. Downregulation of p63 by ZD1839 would identify a potential molecular relationship between EGFR signaling and p63 and could provide insight into the mechanism of action of ZD1839.

STUDY DESIGN - In vitro examination of p63 expression after ZD1839 treatment.

METHODS - A human HNSCC cell line, SCC-012, was treated with varying doses of ZD1839. p63 protein and messenger RNA levels were analyzed by Western and Northern blot analyses. The effect of ZD1839 on SCC-012 cell cycle was analyzed by flow cytometric analysis.

RESULTS - In SCC-012 cells there was a dose-dependent decrease in p63 protein and messenger RNA levels over the course of ZD1839 treatment. Levels of phosphorylated MAPK decreased and p27KIP-1 levels increased after ZD1839 treatment. ZD1839 treatment induced a twofold increase in G1-phase cells and a 3.5-fold decrease in S-phase cells consistent with growth arrest.

CONCLUSION - ZD1839 downregulates p63 expression at the messenger RNA level, suggesting that p63 is a downstream target of EGFR signaling.

MeSH Terms (26)

Antineoplastic Agents Apoptosis Blotting, Northern Blotting, Western Carcinoma, Squamous Cell Cell Division DNA-Binding Proteins Dose-Response Relationship, Drug Down-Regulation ErbB Receptors Flow Cytometry Gefitinib Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Humans Membrane Proteins Mouth Neoplasms Phosphoproteins Protein-Tyrosine Kinases Quinazolines RNA, Messenger Signal Transduction Trans-Activators Transcription Factors Tumor Cells, Cultured Tumor Suppressor Proteins

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