Inhibition of sphingolipid induced apoptosis by caspase inhibitors indicates that sphingosine acts in an earlier part of the apoptotic pathway than ceramide

FEBS Letters
E A SweeneyY Igarashi

Abstract

Caspases are specific proteases involved in apoptosis, and their inhibition by specific peptide inhibitors can inhibit apoptosis. With these inhibitors we examined the relationship of caspases and sphingolipids involved in the induction of apoptosis of human leukemic HL60 cells. We have previously shown that sphingosine (Sph) and its methylated derivative dimethylsphingosine (DMS) effectively induce apoptosis in HL60 cells. Using these lipids as well as ceramide analogues we found both similarities and differences in the caspase involvement in apoptosis induced by the two distinct lipid types. The wide-spectrum caspase inhibitor Z-VAD-FMK and Z-DEVD-FMK, an inhibitor of the downstream caspases 3 (CPP32, Yama) and 7, both inhibited apoptosis induced by all the lipids tested. Z-AAD-FMK which inhibits the serine protease Granzyme B, inhibited Sph/DMS induced apoptosis, but little or no effect on ceramide induced apoptosis. Granzyme B shares a substrate sequence preference with upstream caspases capable of activating themselves and other caspases downstream. Z-IETD-FMK, which inhibits caspase 8/FLICE also inhibited Sph/DMS induced apoptosis with no inhibition of apoptosis induced by either ceramide. Together, these data indicate th...Continue Reading

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