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Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 5/2013

01-06-2013 | Research Paper

Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression

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

Published in: Clinical & Experimental Metastasis | Issue 5/2013

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Abstract

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.
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Metadata
Title
Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression
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
Publication date
01-06-2013
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 5/2013
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-012-9562-5

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