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

作者：C C Bancroft, Zhong Chen, Jason Yeh, John B. Sunwoo, Ning T. Yeh, Sadhana Jackson, Chad R. Jackson, Carter Van Waes · 发表于：International Journal of Cancer · 年份：2002 · DOI：10.1002/ijc.10398 · 被引用次数：231 · 研究领域：HER2/EGFR in Cancer Research、Cytokine Signaling Pathways and Interactions、PI3K/AKT/mTOR signaling in cancer

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. EGFR can activate the phosphotidylinositol-3 kinase (PI3K) and mitogen-activated/extracellular signal-regulated kinase (MEK) pathways, which can potentially modulate activation of NF-kappaB and AP-1, respectively. In our study, we examined the effect of EGF and antagonists of EGFR, PI3K and MEK on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in HNSCC cell lines UM-SCC-9 and 11B in which EGFR is overexpressed and activated. Recombinant EGF induced EGFR phosphorylation, activation of NF-kappaB and AP-1 reporter genes and IL-8 and VEGF expression, indicating that EGFR can mediate coactivation of both transcription factors and cytokine genes in HNSCC. EGFR ant...