Caspase-3 plays key roles in signal transduction cascades that culminate in the development of apoptosis. Since recent studies have reported apoptosis-independent caspase activation, we have investigated agonists-induced activation of caspase-3 independently of apoptosis in two unrelated non-excitable cells, pancreatic acinar cells and platelets. Cell stimulation with agonists, thrombin (1 U/mL) for platelets, or CCK (10^-8 M) for pancreatic acinar cells, for 1 min at 37 ordm;C was able to induce rapid caspase-3 activation independently of rises in cytosolic free Ca²⁺ concentration and the apoptotic pathway, including mitochondrial cytochrome c release and the subsequent activation of caspase-9. In contrast, caspase-3 activation requires PKC activity. Furthermore, we found that rapid caspase-3 activation is necessary for agonist-induced activation of the tyrosine kinases Btk and pp60^src and, subsequently, is required for the initiation of store-operated Ca²⁺ entry in platelets, as well as for full stimulation of a number of cellular functions, including platelet aggregation and pancreatic enzyme secretion. These findings suggest that the involvement of rapid activation of caspase-3 in cellular function is likely a general event in non-excitable mammalian cells.

Supported by MEC-DGI grant BFU2004-00165.