| Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression. | |
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MedLine Citation:
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PMID: 23275034 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-12-30 |
Journal Detail:
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Title: Clinical & experimental metastasis Volume: - ISSN: 1573-7276 ISO Abbreviation: Clin. Exp. Metastasis Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-31 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8409970 Medline TA: Clin Exp Metastasis Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Reproductive Medicine, Moores UCSD Cancer Center, University of California San Diego, 3855 Health Sciences Dr., MC 0803, La Jolla, CA, 92093, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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