Document Detail


FAK inhibition decreases cell invasion, migration and metastasis in MYCN amplified neuroblastoma.
MedLine Citation:
PMID:  23208732     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Michael L Megison; Jerry E Stewart; Hugh C Nabers; Lauren A Gillory; Elizabeth A Beierle
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-12-04
Journal Detail:
Title:  Clinical & experimental metastasis     Volume:  30     ISSN:  1573-7276     ISO Abbreviation:  Clin. Exp. Metastasis     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-24     Completed Date:  2013-07-19     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  8409970     Medline TA:  Clin Exp Metastasis     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  555-68     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Cell Line, Tumor
Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*,  genetics
Gene Silencing
Genes, myc*
Humans
Mice
Neoplasm Invasiveness / prevention & control*
Neoplasm Metastasis / prevention & control*
Neuroblastoma / genetics,  pathology*
Protein Kinase Inhibitors / pharmacology*
RNA, Small Interfering
Grant Support
ID/Acronym/Agency:
K08 CA118178/CA/NCI NIH HHS; K08CA118178/CA/NCI NIH HHS; T32 CA091078/CA/NCI NIH HHS; T32CA091078/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Protein Kinase Inhibitors; 0/RNA, Small Interfering; EC 2.7.10.2/Focal Adhesion Protein-Tyrosine Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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