Saracatinib Impairs Head and Neck Squamous Cell Carcinoma Invasion by Disrupting Invadopodia Function
Amanda Gatesman Ammer1*§, Laura C. Kelley1§, Karen E. Hayes1§, Jason V. Evans1, Lesly Ann Lopez-Skinner1§, Karen H. Martin1, Barbara Frederick2§, Brian L. Rothschild2, David Raben2, Paul Elvin3, Tim P. Green3 and Scott A. Weed1*
- *Corresponding Author:
- Dr. Scott A. Weed
West Virginia University
Mary Babb Randolph Cancer Center
Morgantown, WV, 26508-9300
Received Date: October 28, 2009; Accepted Date: November 30, 2009; Published Date: November 30, 2009
Citation: Ammer AG, Kelley LC, Hayes KE, Evans JV, Lopez-Skinner LA, et al. (2009) Saracatinib Impairs Head and Neck Squamous Cell Carcinoma Invasion by Disrupting Invadopodia Function. J Cancer Sci Ther 1: 052-061. doi:10.4172/1948-5956.1000009
Copyright: © 2009 Ammer AG, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 preclinical 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.