Inhibition of focal adhesion kinase decreases tumor growth in human neuroblastoma.
Neuroblastoma is the most common extracranial solid tumor of childhood. Focal adhesion kinase (FAK) is an intracellular kinase that regulates both cellular adhesion and apoptosis. FAK is overexpressed in a number of human tumors including neuroblastoma. Previously, we have shown that the MYCN oncogene, the primary adverse prognostic indicator in neuroblastoma, regulates the expression of FAK in neuroblastoma. In this study, we have examined the effects of FAK inhibition upon neuroblastoma using a small molecule [1,2,4,5-benzenetetraamine tetrahydrochloride (Y15)] to inhibit FAK expression and the phosphorylation of FAK at the Y397 site. Utilizing both non-isogenic and isogenic MYCN(+)/MYCN(-) neuroblastoma cell lines, we found that Y15 effectively diminished phosphorylation of the Y397 site of FAK. Treatment with Y15 resulted in increased detachment, decreased cell viability and increased apoptosis in the neuroblastoma cell lines. We also found that the cell lines with higher MYCN are more sensitive to Y15 treatment than their MYCN negative counterparts. In addition, we have shown that treatment with Y15 in vivo leads to less tumor growth in nude mouse xenograft models, again with the greatest effects seen in MYCN(+) tumor xenografts. The results of the current study suggest that FAK and phosphorylation at the Y397 site plays a role in neuroblastoma cell survival, and that the FAK Y397 phosphorylation site is a potential therapeutic target for this childhood tumor.
Beierle
Elizabeth A
EA
Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, USA. elizabeth.beierle@ccc.uab.edu
Ma
Xiaojie
X
Stewart
Jerry
J
Nyberg
Carl
C
Trujillo
Angelica
A
Cance
William G
WG
Golubovskaya
Vita M
VM
D000814:Aniline Compounds / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C539551:1,2,4,5-benzenetetraamine; D000814:Aniline Compounds; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases