Differential regulation of extrinsic and intrinsic cell death pathways by protein kinase C.

The pathway of cell death depends on the apoptotic stimuli as well as on the cell type. In the present study, we have compared how extrinsic and intrinsic cell death pathways are regulated by the protein kinase C (PKC) signal transduction pathway in the same cell type. PDBu, an activator of PKC, potentiated cell death mediated by the DNA damaging agent cisplatin but it blocked tumor necrosis factor-alpha (TNF)-induced cell death in HeLa cells. Conversely, rottlerin, an inhibitor of PKCdelta, decreased sensitivity of HeLa cells to cisplatin but it potentiated TNF-induced cell death. Although both TNF and cisplatin caused activation of caspases, PKC modulators had opposing effects on caspase activation. Rottlerin inhibited mitochondrial or intrinsic cell death pathway by inhibiting cisplatin-induced processing of apical caspase-9 and its downstream caspases. In contrast, it potentiated receptor-initiated or extrinsic cell death pathway by enhancing activation of caspase-2 and/or caspase-8. These results suggest that PKC acts at distinct steps to regulate receptor-mediated and DNA damage-induced apoptosis.