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 d own-regulate FAK function in normal and transformed mammary cells, we have used adenoviral gene transduction of the carboxyl-terminal domain of FAK (F AK-CD). Transduction of adenovirus containing FAH-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 t hat FAK is a survival signal in breast tumor cells even in the absence of m atrix signaling. In addition, both anchorage-dependent and anchorage-indepe ndent 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 c ells, despite the loss of tyrosine phosphorylation of p125(FAK). These resu lts indicate that FAK-mediated signaling is required for both cell adhesion and anchorage-independent survival and the disruption of FAK function invo lves the Fas-associated death domain and caspase-8 apoptotic pathway.