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(Received for publication, June 9, 1997)
From the Division of Cellular Biochemistry, The Netherlands Cancer
Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
The current confusion regarding the relevance of
endogenous ceramide in mediating CD95/Fas-induced apoptosis is based
mainly on (i) discrepancies in kinetics of the ceramide response
between different studies using the same apoptotic stimulus and (ii)
the observation that late ceramide formation (hours) often parallels apoptosis onset. We investigated CD95-induced ceramide formation in
Jurkat cells, using two methods (radiolabeling/thin layer
chromatography and benzoylation/high performance liquid
chromatography), which, unlike the commonly used diglyceride kinase
assay, discriminate between ceramide species and de novo
formed dihydroceramide. We demonstrate that ceramide accumulates after
several hours, reaching a 7-fold increase after 8 h, kinetics
closely paralleling apoptosis induction. No fast response was observed,
not even in the presence of inhibitors of ceramide metabolism. The
majority (~70%) of the ceramide response remained unaffected when
apoptosis was completely inhibited at the level of caspase-3/CPP32
processing by the inhibitor peptide DEVD-CHO. Exogenous cell-permeable
C2-ceramide induced the proteolytic processing of
caspase-3, albeit with somewhat slower kinetics than with CD95.
DEVD-CHO dose-dependently inhibited C2-ceramide- or exogenous sphingomyelinase-induced
apoptosis. The results support the idea that ceramide acts in
conjunction with the caspase cascade in CD95-induced apoptosis.
Volume 272, Number 39,
Issue of September 26, 1997
pp. 24308-24312
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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