Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines.

We previously reported that expression of angiogenesis factors interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) is promoted by coactivation of transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) by interleukin-1alpha in human head and neck squamous cell carcinomas (HNSCC). However, expression of IL-1 receptor antagonist incompletely blocked reporter gene activity and cytokine expression, suggesting that other upstream signals may contribute to activation. Overexpression and autocrine activation of epidermal growth factor receptor (EGFR) is detected in 90% of HNSCC, and EGFR inhibitors have been reported to inhibit IL-8 and VEGF expression, but the intermediary signal pathways and transcription factors by which EGFR modulates proangiogenic factors is unknown.