Despite their individual key roles in promoting
head and neck squamous cell carcinoma (
HNSCC) progression and treatment resistance, little is known about the impact of intratumoral
hypoxia on the activity of the
epidermal growth factor receptor (EGFR) signaling pathway in this
cancer type. Here, we show that in highly EGFR-expressing
HNSCC cells, hypoxic stress triggers the activation of the EGFR and downstream targets, including Akt and
phospholipase C (
PLC) gamma1. In support of these findings, we also demonstrate that EGFR activation takes place within hypoxic foci in a subset of human
HNSCC tissues. Whereas
hypoxia had no major effect on
HNSCC cell proliferation, it markedly altered
tumor cell shape by inducing morphological changes consistent with a more spindle-shaped, fibroblast-like morphology together with an enhanced migratory capacity. We found that
hypoxia-induced EGFR activation and cell migration could be prevented by targeting EGFR signaling with the
tyrosine kinase inhibitor tyrphostin, the
phospholipase C inhibitor
U73122, or by inhibiting the expression of the alpha subunit of
hypoxia-inducible factor 2 via RNA interference or the
topoisomerase II inhibitor etoposide. Our results position
hypoxia-inducible factor-2alpha as a novel regulator of EGFR activation under low
oxygen conditions, and suggest that
hypoxia-induced EGFR signaling may promote a more aggressive phenotype in a fraction of
HNSCC tumors. Because EGFR continues in the forefront as a highly attractive target in clinical oncology, further studies are warranted to define the mechanistic and therapeutic implications of the hypoxic response relative to the EGFR signaling pathway in
head and neck cancer.