CPP32 INHIBITION PREVENTS FAS-INDUCED CERAMIDE GENERATION AND APOPTOSIS IN HUMAN-CELLS

Intracellular activation of sphingomyelinase, leading to ceramide gene ration, and ICE-like proteases have been implicated in TNF and Fas-ind uced apoptosis, but the links between these intracellular apoptotic me diators remain undefined, We show here that a specific peptide inhibit or of the ICE-like protease CPP32/Yama (DEVD-CHO) blocks anti-Fas-indu ced apoptosis in Jurkat and U937 cells, while having no effect on TNF- induced apoptosis in U937 cells. This peptide also prevents ceramide a ccumulation induced by Pas engagement, Jurkat and U937 cells, as web a s their mtDNA-depleted derived lines (rho degrees cells), were sensiti ve to ceramide toxicity, which was not prevented by ICE-like protease inhibitors. These results, taken together, suggest that ICE-like prote ase activation is a prerequisite for ceramide generation and subsequen t apoptosis, at least in the case of Fas-induced cell death.