TY - JOUR
T1 - FAK inhibition decreases hepatoblastoma survival both in vitro and in vivo
AU - Gillory, Lauren A.
AU - Stewart, Jerry E.
AU - Megison, Michael L.
AU - Nabers, Hugh C.
AU - Mroczek-Musulman, Elizabeth
AU - Beierle, Elizabeth A.
N1 - Funding Information:
Address all correspondence to: Elizabeth A. Beierle, MD, 1600 7th Avenue South, Lowder Building, Room 300, Birmingham, AL 35233. E-mail: elizabeth.beierle@childrensal.org 1This work was supported by grants from the National Cancer Institute [T32CA091078 to L.A.G. and M.L.M. and K08CA118178 to E.A.B.]. 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. Conflict of Interest Statement: None declared. 2This article refers to supplementary material, which is designated by Figure W1 and is available online at www.transonc.com. Received 27 December 2012; Revised 29 January 2013; Accepted 29 January 2013 Copyright © 2013 Neoplasia Press, Inc. Open access under CC BY-NC-ND license. 1944-7124/13 DOI 10.1593/tlo.12505
PY - 2013/4
Y1 - 2013/4
N2 - Hepatoblastoma is the most frequently diagnosed liver tumor of childhood, and children with advanced, metastatic or relapsed disease have a disease-free survival rate under 50%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult hepatocellular carcinoma, leading us to hypothesize that FAK would be present in hepatoblastoma and would impact its cellular survival. In the current study, we showed that FAK was present and phosphorylated in human hepatoblastoma tumor specimens. We also examined the effects of FAK inhibition upon hepatoblastoma cells using a number of parallel approaches to block FAK including RNAi and small molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion, and migration and increased apoptosis. Further, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse xenograft model of hepatoblastoma. The findings from this study will help to further our understanding of the regulation of hepatoblastoma tumorigenesis and may provide desperately needed novel therapeutic strategies and targets for aggressive, recurrent, or metastatic hepatoblastomas.
AB - Hepatoblastoma is the most frequently diagnosed liver tumor of childhood, and children with advanced, metastatic or relapsed disease have a disease-free survival rate under 50%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult hepatocellular carcinoma, leading us to hypothesize that FAK would be present in hepatoblastoma and would impact its cellular survival. In the current study, we showed that FAK was present and phosphorylated in human hepatoblastoma tumor specimens. We also examined the effects of FAK inhibition upon hepatoblastoma cells using a number of parallel approaches to block FAK including RNAi and small molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion, and migration and increased apoptosis. Further, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse xenograft model of hepatoblastoma. The findings from this study will help to further our understanding of the regulation of hepatoblastoma tumorigenesis and may provide desperately needed novel therapeutic strategies and targets for aggressive, recurrent, or metastatic hepatoblastomas.
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U2 - 10.1593/tlo.12505
DO - 10.1593/tlo.12505
M3 - Article
C2 - 23544173
AN - SCOPUS:84875799324
SN - 1936-5233
VL - 6
SP - 206
EP - 215
JO - Translational Oncology
JF - Translational Oncology
IS - 2
ER -