Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8

Although caspase-2 is believed to be involved in death receptor-mediated Apoptosis, the exact function, mode of activation, and regulation of caspase-2 remain unknown. Here we show that protein kinase (PK) CK2 phosphorylates procaspase-2 directly at serine-157. When intracellular PKCK2 activity is low or downregulated by specific inhibitors, procaspase-2 is dephosphorylated, dimerized, and activated in a PIDDosome-independent manner. The activated caspase-2 then processes procaspase-8 monomers between the large and small subunits, thereby priming Cancer cells for TNF-related apoptosis-inducing ligand (TRAIL)-mediated Apoptosis. The processed procaspase-8 that is recruited to death-inducing signaling complex by TRAIL engagement becomes fully activated, and Cancer cells undergo Apoptosis. PKCK2 activity is low in TRAIL-sensitive Cancer cell lines but high in TRAIL-resistant Cancer cell lines. Thus, downregulating PKCK2 activity is required for TRAIL-mediated Apoptosis to occur in TRAIL-resistant Cancer cells. Our data provide novel insights into the regulation, mode of activation, and function of caspase-2 in TRAIL-mediated Apoptosis.