Saracatinib Impairs Head and Neck Squamous Cell Carcinoma Invasion by Disrupting Invadopodia Function

Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, 26506-9300.
Journal of Cancer Science and Therapy 11/2009; 1(2):52-61. DOI: 10.4172/1948-5956.1000009
Source: PubMed


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.

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    • "Together, these two studies provide clues that the ability of flavonoids to inhibit MMP secretion might be owing to the inhibition of invadopodia formation. Ammer et al. showed that inhibition of Src kinase results in inhibition of MMP-9′s secretion, causing an accumulation of MMP-9 in HNSCC cell lines [48]. Moreover, MMPs have to be recruited to the invadopodia in order to accomplish the degradation of the matrix. "
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    • "Several molecular target drugs that are already used in clinics or tested in preclinical or clinical trials may be used for targeting invadopodia formation. The small molecule Src/Abl inhibitors, saracatinib and dasatinib, block invadopodia-mediated invasion of head and neck cancer cells and breast cancer cells, respectively (Ammer et al., 2009; Pichot et al., 2009). We also reported that Iressa, a small molecule EGF-receptor inhibitor, blocks EGF-dependent invadopodia formation in breast cancer cells (Yamaguchi et al., 2005a). "
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    • "In HNSCC and several other tumor types, cortactin is present in the cytoplasm and is enriched at cell-cell junctions [48], [60], [61]. The localization of pS418 cortactin at regions of HNSCC cellular contact within tumors resembles the localization pattern of pY421 cortactin in this tumor type [62]. The staining pattern of cortactin and its tyrosine phosphorylated form is reminiscent of that found in two-dimensional epithelial monolayers, where cortactin has been shown to be essential for Arp2/3-mediated actin remodeling resultant from E-cadherin homoligation and subsequent Src activity [63], [64]. "
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