FAK Inhibition Decreases Neuroblastoma Cell Invasion, Migration and Metastasis
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Megison, Michael L., Stewart, Jerry E., Gillory, Lauren A., Nabers, Hugh and Beierle, Elizabeth A. (2013) FAK Inhibition Decreases Neuroblastoma Cell Invasion, Migration and Metastasis. Clinical and Experimental Metastasis, 30 (5). pp. 555-568. ISSN 0262-0898
Abstract
Neuroblastoma, the most common extracranial solid tumor of childhood, is responsible for over 15% of pediatric cancer deaths. We have shown that neuroblastoma cell lines overexpress focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase that controls a number of tumorigenic pathways. In this study, we hypothesized that inhibition of FAK would result in decreased cellular migration and invasion in neuroblastoma cell lines, and decrease metastasis in a murine model.
We utilized multiple human neuroblastoma cell lines and three different methods of FAK inhibition. Cell viability, migration, and invasion assays were employed to assess the effects of FAK inhibition in vitro. A nude mouse model was utilized to determine the effects of FAK inhibition on in vivo liver metastasis.
Abrogation of FAK with two small molecule inhibitors, 1,2,4,5-benzenetetraamine tetrahydrochloride (Y15) and NVP-TAE226 (TAE), resulted in decreased cell survival, migration and invasion in neuroblastoma cell lines. FAK knockdown with siRNA also resulted in decreased invasion and migration in neuroblastoma cell lines. Furthermore, the effects of FAK inhibition were more pronounced in the MYCN amplified cell lines. Finally, inhibition of FAK with Y15 or TAE in a nude mouse model resulted in a significant decrease in tumor burden in SK-N-BE(2) injected animals.
We believe that FAK plays an important role in the metastatic phenotype of neuroblastoma cells that is exaggerated in cell lines that overexpress MYCN. Inhibition of FAK in these cell lines significantly decreased the malignant potential of these cells. FAK inhibition warrants further investigation as a potential therapeutic target in the treatment of aggressive neuroblastoma.
| Item Type: | Article |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/7737 |