Open AccessSaracatinib Impairs Head and Neck Squamous Cell Carcinoma Invasion by Disrupting Invadopodia Function
Author(s) -
Amanda G. Ammer,
Laura C. Kelley,
Kevin Hayes,
Jason V. Evans,
Lesly Ann Lopez-Skinner,
Karen H. Martin,
Barbara Frederick,
Brian Rothschild,
David Raben,
Paul Elvin,
Tim P. Green,
Scott A. Weed
Publication year - 2009
Publication title -
journal of cancer science and therapy
Language(s) - English
Resource type - Journals
ISSN - 1948-5956
DOI - 10.4172/1948-5956.1000009
Subject(s) - invadopodia , cortactin , head and neck squamous cell carcinoma , cancer research , proto oncogene tyrosine protein kinase src , extracellular matrix , medicine , metastasis , focal adhesion , cell migration , cell growth , pathology , cell , phosphorylation , cancer , microbiology and biotechnology , biology , head and neck cancer , receptor , biochemistry , cytoskeleton
Elevated Src kinase activity is linked to the progression of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Src regulates HNSCC proliferation and tumor invasion, with the Src-targeted small molecule inhibitor saracatinib displaying potent anti-invasive effects in preclinical studies. However, the pro-invasive cellular mechanism(s) perturbed by saracatinib are unclear. The anti-proliferative and anti-invasive effects of saracatinib on HNSCC cell lines were therefore investigated in pre-clinical cell and mouse model systems. Saracatinib treatment inhibited growth, cell cycle progression and transwell Matrigel invasion in HNSCC cell lines. Dose-dependent decreases in Src activation and phosphorylation of the invasion-associated substrates focal adhesion kinase, p130 CAS and cortactin were also observed. While saracatinib did not significantly impact HNSCC tumor growth in a mouse orthotopic model of tongue squamous cell carcinoma, impaired perineural invasion and cervical lymph node metastasis was observed. Accordingly, saracatinib treatment displayed a dose-dependent inhibitory effect on invadopodia formation, extracellular matrix degradation and matrix metalloprotease 9 activation. These results suggest that inhibition of Src kinase by saracatinib impairs the pro-invasive activity of HNSCC by inhibiting Src substrate phosphorylation important for invadopodia formation and associated matrix metalloprotease activity.