title: FAK inhibition decreases cell invasion, migration and metastasis in MYCN amplified neuroblastoma.
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.
authors.affiliation: University of Alabama, Birmingham, AL, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Megison
authors.forename: Jerry E
authors.initials: JE
authors.lastname: Stewart
authors.forename: Hugh C
authors.initials: HC
authors.lastname: Nabers
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Gillory
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Beierle
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D020868:Gene Silencing; D016259:Genes, myc; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering
chemical_list: D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D051416:Focal Adhesion Protein-Tyrosine Kinases