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Cancer Biology, Immunology, Cytokines |
B Signal Pathways1
Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892-1419
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)-
B and activator
protein-1 (AP-1), which we showed previously are coactivated in HNSCCs.
NF-B and AP-1 may be modulated by the inhibitor B 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-B by
expression of an inhibitor B
mutant (IBM) 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--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-B and AP-1, and U0126 inhibited both
NF-B 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-B 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.
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