The focal adhesion kinase suppresses transformation-associated, anchorage-independent apoptosis in human breast cancer cells. Involvement of death receptor-related signaling pathways.
The focal adhesion kinase (FAK) is a mediator of cell-extracellular matrix signaling events and is overexpressed in tumor cells. In order to rapidly down-regulate FAK function in normal and transformed mammary cells, we have used adenoviral gene transduction of the carboxyl-terminal domain of FAK (FAK-CD). Transduction of adenovirus containing FAK-CD in breast cancer cells caused loss of adhesion, degradation of p125(FAK), and induced apoptosis. Furthermore, breast tumor cells that were viable without matrix attachment also underwent apoptosis upon interruption of FAK function, demonstrating that FAK is a survival signal in breast tumor cells even in the absence of matrix signaling. In addition, both anchorage-dependent and anchorage-independent apoptotic signaling required Fas-associated death domain and caspase-8, suggesting that a death receptor-mediated apoptotic pathway is involved. Finally, FAK-CD had no effect on adhesion or viability in normal mammary cells, despite the loss of tyrosine phosphorylation of p125(FAK). These results indicate that FAK-mediated signaling is required for both cell adhesion and anchorage-independent survival and the disruption of FAK function involves the Fas-associated death domain and caspase-8 apoptotic pathway.
Xu
L H
LH
Departments of Surgery, Medicine, and Biology and The Lineberger Comprehensive Cancer Center, the University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Yang
X
X
Bradham
C A
CA
Brenner
D A
DA
Baldwin
A S
AS
Craven
R J
RJ
Cance
W G
WG
D017209:Apoptosis; D001943:Breast Neoplasms; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
D061945:Caspase Inhibitors; D019014:fas Receptor; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases