Abstract
Focal adhesion kinase (FAK) and Src have been shown to be overexpressed in colon cancer. We have studied the role of these two kinases in resistance to apoptosis. Adenovirus-containing FAK-CD (Ad-FAK-CD), a dominant-negative, COOH-terminal portion of FAK, was used to inhibit FAK and cause apoptosis. Colon cancer cell lines were more resistant to Ad-FAK-CD-induced detachment and apoptosis than the breast cancer cell line, BT474. Colon cancer cell lines overexpressed highly active Src and FAK. Ad-FAK-CD-induced apoptosis was significantly increased by PP2, an inhibitor of Src family kinases. Activation of caspase-3, down-regulation of FAK, and Src and AKT activities were demonstrated in Ad-FAK-CD + PP2-treated colon cancer cells undergoing apoptosis. The results suggest that FAK and Src are both important survival factors, playing a role in protecting colon cancer cell lines from Ad-FAK-CD-induced apoptosis. Dual inhibition of these kinases may be important for therapies designed to enhance the apoptosis in colon cancers.
MeSH terms
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Adenoviridae / genetics
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Adenoviridae / metabolism
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Apoptosis / drug effects
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Apoptosis / physiology*
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Blotting, Western
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Caspase 3
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Caspases / metabolism
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Cell Adhesion* / drug effects
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Cell Line, Tumor
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Down-Regulation
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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HT29 Cells
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Humans
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Immunoblotting
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Microscopy, Fluorescence
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Protein Serine-Threonine Kinases*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Pyrimidines / pharmacology
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Signal Transduction
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Staurosporine / pharmacology
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / metabolism*
Substances
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AG 1879
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Proto-Oncogene Proteins
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Pyrimidines
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Protein-Tyrosine Kinases
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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PTK2 protein, human
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src-Family Kinases
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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CASP3 protein, human
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Caspase 3
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Caspases
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Staurosporine