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FAK inhibition decreases cell invasion, migration and metastasis in MYCN amplified neuroblastoma

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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 non-isogenic and isogenic MYCN human neuroblastoma cell lines and parallel 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. FAK knockdown with siRNA resulted in decreased invasion and migration in neuroblastoma cell lines, and the effects of siRNA-induced FAK inhibition were more pronounced in MYCN amplified cell lines. In addition, abrogation of FAK with a small molecule inhibitors resulted in decreased cell survival, migration and invasion in neuroblastoma cell lines, again most pronounced in cell lines with MYCN amplification. Finally, small molecule FAK inhibition in a nude mouse model resulted in a significant decrease in metastatic tumor burden in SK-N-BE(2) injected animals. We believe that FAK plays an important role in maintaining and propagating the metastatic phenotype of neuroblastoma cells, and this driver role is exaggerated in cell lines that overexpress MYCN. FAK inhibition warrants further investigation as a potential therapeutic target in the treatment of aggressive neuroblastoma.

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Abbreviations

EDTA:

Ethylenediaminetetraacetic acid

FAK:

Focal adhesion kinase

NaDOC:

Sodium deoxycholate

PMFS:

Phenylmethanesulfonylfluoride

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Acknowledgments

The authors would like to thank Dr. Schwab for his kind gift of the SH-EP and WAC2 cell lines. The authors were supported in part by grants from the National Cancer Institute including MM, LG, (Grant Number T32CA091078) and EAB (Grant Number K08CA118178). The content of this manuscript was solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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The authors have no conflict of interest.

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Authors and Affiliations

  1. University of Alabama, Birmingham, AL, USA

    Michael L. Megison, Jerry E. Stewart, Hugh C. Nabers, Lauren A. Gillory & Elizabeth A. Beierle

  2. 1600 7th Avenue South, Lowder Building, Room 300, Birmingham, AL, 35233, USA

    Elizabeth A. Beierle

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  1. Michael L. Megison
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Correspondence to Elizabeth A. Beierle.

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Megison, M.L., Stewart, J.E., Nabers, H.C. et al. FAK inhibition decreases cell invasion, migration and metastasis in MYCN amplified neuroblastoma. Clin Exp Metastasis 30, 555–568 (2013). https://doi.org/10.1007/s10585-012-9560-7

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  • DOI: https://doi.org/10.1007/s10585-012-9560-7

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