Coexpression of Proangiogenic Factors IL-8 and VEGF by Human Head and Neck Squamous Cell Carcinoma Involves Coactivation by MEK-MAPK and IKK-NF-κB Signal Pathways

• Published in: Clinical cancer research 2001-02, Vol.7 (2), p.435
• Main Authors: Caren C. Bancroft, Zhong Chen, Gang Dong, John B. Sunwoo, Ning Yeh, Catherine Park, Carter Van Waes
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265

Interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) promote tumor angiogenesis, growth, and metastasis and are coexpressed by human head and neck squamous cell carcinomas (HNSCCs) and a variety of other cancers. The promoters of the IL-8 and VEGF genes contain different recognition sites for transcription factors nuclear factor (NF)-κB and activator protein-1 (AP-1), which we showed previously are coactivated in HNSCCs. NF-κB and AP-1 may be modulated by the inhibitor κB kinase (IKK) and mitogen-activated protein kinase (MAPK) signal pathways, but the contribution of these pathways to expression of IL-8 and VEGF and as potential targets for antiangiogenesis therapy in HNSCC is not known. In this study, we examined the effects of modulation of the MAPK and IKK pathways on expression of IL-8 and VEGF by UM-SCC-9 and UM-SCC-11B cell lines. Interruption of IKK-mediated activation of NF-κB by expression of an inhibitor κBα mutant (IκBαM) in UM-SCC-9 cells resulted in partial inhibition of expression of IL-8 but not VEGF. Analysis of possible alternative pathways for induction of these genes revealed activation of the MAPK extracellular signal-regulated kinase (ERK1/2) in cell lines UM-SCC-9 and UM-SCC-11B. Basal and tumor necrosis factor-α-inducible phosphorylation of ERK1/2 and secretion of IL-8 and VEGF could be specifically inhibited by a MEK inhibitor, U0126. Expression of IL-8 and VEGF in the cell lines was associated with coactivation of both NF-κB and AP-1, and U0126 inhibited both NF-κB and AP-1 reporter activity in UM-SCC-9 and UM-SCC-11B cells. The ERK pathway appears to contribute to expression of IL-8 and VEGF and transactivation of NF-κB as well as AP-1 in HNSCC. Combined inhibition of both MAPK and IKK pathways may be needed for suppression of the signal transduction mechanism(s) regulating VEGF and IL-8 secretion and angiogenesis by human HNSCC.