Loss of Caspase-8 in Tumor Cells: Mechanism to Overcome Integrin-Mediated Death?

Simplified schematic of apoptosis pathways focused on integrin-mediated death (IMD). Integrins ligated by the appropriate ligands serve to mediate cell survival pathways (purple). In their unligated or antagonized state, integrins promote the recruitment and activation of caspase-8 at the cell surface. This results in initiation of the IMD pathway (red), which occurs independently of the death receptor-mediated extrinsic pathway (blue) or stress-induced intrinsic pathway (green). Integrin antagonism can potentiate caspase-8 activity by activating protein kinase A (PKA), which in turn activates caspase-8, or by suppressing the expression of inhibitors, c-FLIP and bcl-2. c-FLIP, Fas-associated death domain–like interleukin 1β–converting enzyme (FLICE)-inhibitory protein.