Concentration and distribution of individual endogenous
ceramide species is crucial for apoptosis induction in response to various stimuli. Exogenous
ceramide analogs induce apoptosis and can in turn modify the composition/concentrations of endogenous
ceramide species and associated signaling. In this study, we show here that the elevation of endogenous
C16-ceramide levels is a common feature of several known apoptosis-inducing triggers like mmLDL,
TNF-alpha, H2O2 and exogenous
C6-ceramide. Vice versa apoptosis requires elevation of endogenous
C16-ceramide levels in cells. Enantiomers of a synthetic
ceramide analog HPL-1RS36N have been developed as probes and vary in their capacity to inducing apoptosis in macrophages and HT-29 cells. Apoptosis induction by the two synthetic
ceramide analogs HPL-39N and HPL-1R36N correlates with generation of cellular
C16-ceramide concentration. In contrast to the S-enantiomer HPL-1S36N, the R-enantiomer HPL-1R36N shows significant effects on the expression of distinct genes known to be involved in cell cycle, cell growth and cell death (CXCL10, CCL5 and
TNF-alpha), similarly on apoptosis induction. Enantioselective effects on transcription induced by metabolically stable synthetic probes provide clues on molecular mechanisms of
ceramide-induced signaling, as well as leads for future anti-
cancer agents.