期刊
CELL DEATH AND DIFFERENTIATION
卷 8, 期 6, 页码 595-602出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4400848
关键词
ceramide; CD95 (APO-1, Fas); glioma; apoptosis; caspases
Most human malignant glioma cell lines are susceptible to CD95 ligand (CD95L)-induced apoptosis, Here, we report that glioma cells are also susceptible to the cytotoxic effects of exogenous C2-ceramide. This form of cell death exhibits some morphological features of apoptosis as assessed by electron microscopy, but is unaffected by the broad spectrum caspase inhibitor, zVAD-fmk. Further, CD95L-induced apoptosis is synergistically enhanced by coexposure of the glioma cells to CD95L and CP-ceramide. CD95L-induced caspase 3-like activity, cytochrome c release and cleavage of caspases 3, 8, 9 and poly(ADP-ribose)polymerase (PARP) increase substantially after cotreatment with CD95L and CS-ceramide compared with CD95L treatment alone. None of these events occur in response to cytotoxic concentrations of CS-ceramide alone. C2-ceramide does not alter CD95 expression. Gene transfer-mediated enhancement of CD95 expression results not only in increased susceptibility to CD95L, but also in increased sensitivity to CS-ceramide. We conclude that (i) synergistic induction of apoptos is by CP-ceramide and CD95 L depend on a cross-talk between the two signal transduction pathways and that (ii) CP ceramide, independently of its sensitizing effects on CD95-dependent caspase activation, is also capable of triggering an apoptotic signaling cascade that is unaffected by zVAD-fmk-mediated caspase inhibition, but promoted by high levels of CD95 expression.
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