Document Detail


Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression.
MedLine Citation:
PMID:  23275034     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recurrence and spread of ovarian cancer is the 5th leading cause of death for women in the United States. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase located on chromosome 8q24.3 (gene is Ptk2), a site commonly amplified in serous ovarian cancer. Elevated FAK mRNA levels in serous ovarian carcinoma are associated with decreased (logrank P = 0.0007, hazard ratio 1.43) patient overall survival, but how FAK functions in tumor progression remains undefined. We have isolated aggressive ovarian carcinoma cells termed ID8-IP after intraperitoneal (IP) growth of murine ID8 cells in C57Bl6 mice. Upon orthotopic implantation within the peri-ovarian bursa space, ID8-IP cells exhibit greater tumor growth, local and distant metastasis, and elevated numbers of ascites-associated cells compared to parental ID8 cells. ID8-IP cells exhibit enhanced growth under non-adherent conditions with elevated FAK and c-Src tyrosine kinase activation compared to parental ID8 cells. In vitro, the small molecule FAK inhibitor (Pfizer, PF562,271, PF-271) at 0.1 uM selectively prevented anchorage-independent ID8-IP cell growth with the inhibition of FAK tyrosine (Y)397 but not c-Src Y416 phosphorylation. Oral PF-271 administration (30 mg/kg, twice daily) blocked FAK but not c-Src tyrosine phosphorylation in ID8-IP tumors. This was associated with decreased tumor size, prevention of peritoneal metastasis, reduced tumor-associated endothelial cell number, and increased tumor cell-associated apoptosis. FAK knockdown and re-expression assays showed that FAK activity selectively promoted anchorage-independent ID8-IP cell survival. These results support the continued evaluation of FAK inhibitors as a promising clinical treatment for ovarian cancer.
Authors:
Kristy K Ward; Isabelle Tancioni; Christine Lawson; Nichol L G Miller; Christine Jean; Xiao Lei Chen; Sean Uryu; Josephine Kim; David Tarin; Dwayne G Stupack; Steven C Plaxe; David D Schlaepfer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-30
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:  2014-03-27    
Medline Journal Info:
Nlm Unique ID:  8409970     Medline TA:  Clin Exp Metastasis     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  579-94     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Cell Division / drug effects*
Disease Progression*
Female
Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*,  genetics
Humans
Ovarian Neoplasms / enzymology,  pathology*
Protein Kinase Inhibitors / pharmacology*
RNA, Messenger / genetics
Grant Support
ID/Acronym/Agency:
1F32CA159558/CA/NCI NIH HHS; 200810MFE-193594-139144//Canadian Institutes of Health Research; CA102310/CA/NCI NIH HHS; CA107263/CA/NCI NIH HHS; F32 CA159558/CA/NCI NIH HHS; GM087400/GM/NIGMS NIH HHS; R01 CA102310/CA/NCI NIH HHS; R01 CA107263/CA/NCI NIH HHS; R01 GM087400/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Protein Kinase Inhibitors; 0/RNA, Messenger; EC 2.7.10.2/Focal Adhesion Protein-Tyrosine Kinases

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


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