Apoptosis ceramide-regulated

A variety of studies demonstrate a central role for ASM and ceramide in several forms of apoptosis. Ceramide seems to regulate the activity of certain proteins and, thus, may function, in some circumstances, as a second messenger. In addition, the concept of raft modification hy ceramide provides a comprehensive model for cellular effects of ceramide, and perhaps a biophysical explanation for the diverse functions of this lipid. 

Recently, it has been shown that cell-permeable ceramides dramatically inhibited the synthesis of the two major membrane phospholipids, PC and PE (Bladergroen et al, 1999b Allan, 2000). The inhibition of phospholipid synthesis was rapid, within 2 h, and resulted in massive apoptosis after 16-24 h. The mechanism by which short-chain ceramides exert their effect on phospholipid synthesis is possibly cell type dependent. In baby-hamster kidney (BHK) fibroblasts PC synthesis was reduced at the level of CT, the putative rate-determining enzyme in the CDP-choline pathway (Allan, 2000). This conclusion was based solely on radio-label studies in combination with an earlier published observation (Wieder et al., 1995) showing that C2-SM (the SM generated from C2-ceramide by SM synthase, which was actively synthesized in the BHK-cells) inhibited CT activity in vitro. On the other hand, data obtained from studies with rat-2 fibroblasts clearly showed that short-chain ceramides regulate the synthesis of PC and PE mainly at the final step of the CDP-pathways. This conclusion was based on the following observations (a) incorporation of [3H]-choline into PC and... 

Gulbins, E. Regulation of death receptor signaling and apoptosis by ceramide. Pharmacol. Res. 47 393-399,2003. 

Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process. In many cases proteins and/or lipid mediators that induce changes in mitochondrial membrane permeability and calcium regulation are produced or activated. For example, the pro-apoptotic Bcl-2 family members Bax, Bad and Bid may associate with the mitochondrial membrane and modify its permeability. Membrane-derived lipid mediators such as ceramide and 4-hydroxynonenal can also induce mitochondrial membrane alterations that are critical for the execution of apoptosis. 

Perry, D.K., Carton, J., Shah, A.K., Meredith, F., Uhlinger, D.J., and Hannun, Y.A., 2000, Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J. Biol. Chem. 275 9078-9084. 

While the exact mechanism of ceramide-mediated regulation of most of the above proteins is still unknown, ASM-released ceramide binds directly to PLAa and cathepsin D (Huwiler et al, 2001 Heinrich et al., 1999). Binding of ceramide to cathepsin D in endosomes triggers autocatalytic cleavage of cathepsin to its active form (Heinrich et al, 1999). However, the physiological role of ceramide binding to cathepsin D and PLA2 for apoptosis stiU remains to be determined. 

Brenner, B., Koppenhoefer, U., Weinstock, C., Linderkamp, O., Lang, F. and Gulbins, E., 1997, Fas- or ceramide-induced apoptosis is mediated by a Rad-regulated activation of Jun N-terminalkinase/p38 kinases and GADD153./. Biol. Chem. 272 22173-22181... 

Figure 15.4 Mechanisms of apoptosis induction by resveratrol. Resveratrol selectively induces apoptosis in various cancer cells in culture by several mechanisms including activation of death receptor-mediated signaling, mitochondria-dependent cytochrome c release and caspase activation, induction of p53 and p53-regulated proapototic genes, activation of MAP kinase-mediated p53 phosphorylation, blockade of Akt-mediated cell survival pathways, and accumulation of intracellular ceramide level.

---