title: Saracatinib Impairs Head and Neck Squamous Cell Carcinoma Invasion by Disrupting Invadopodia Function.
abstract: 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.
authors.affiliation: Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, 26506-9300.
authors.forename: Amanda Gatesman
authors.initials: AG
authors.lastname: Ammer
authors.forename: Laura C
authors.initials: LC
authors.lastname: Kelley
authors.forename: Karen E
authors.initials: KE
authors.lastname: Hayes
authors.forename: Jason V
authors.initials: JV
authors.lastname: Evans
authors.forename: Lesly Ann
authors.initials: LA
authors.lastname: Lopez-Skinner
authors.forename: Karen H
authors.initials: KH
authors.lastname: Martin
authors.forename: Barbara
authors.initials: B
authors.lastname: Frederick
authors.forename: Brian L
authors.initials: BL
authors.lastname: Rothschild
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.forename: Paul
authors.initials: P
authors.lastname: Elvin
authors.forename: Tim P
authors.initials: TP
authors.lastname: Green
authors.forename: Scott A
authors.initials: SA
authors.lastname: Weed