Ceramide and apoptosis

Kolesnick R, Hannun YA (1999) Ceramide and apoptosis. Trends Biochem Sci 282 224-225... 

The above examples point out at the direct stimulation of apoptosis by nitric oxide. At the same time, the exclusively rapid reaction of NO with superoxide always suggests the possibility of peroxynitrite participation in this process [141] correspondingly, the role peroxynitrite in the stimulation of apoptosis has been considered. Bonfoco et al. [144] has found that the producers of low peroxynitrite concentrations during the exposure of cortical neurons to the low level of NMDA or the use of peroxynitrite donors resulted in an apoptosis in neurons, while the high concentrations of peroxynitrite induced necrotic cell damage. The formation of peroxynitrite is apparently responsible for NO-stimulated apoptosis in superoxide-generating transformed fibroblasts because nontransformed cells, which do not produce superoxide, were not affected by nitric oxide [145]. It is of interest that proapoptotic effect of peroxynitrite may depend on the cell type. Thus, the formation of peroxynitrite enhanced the NO-induced apoptosis in glomerular endothelial cells, while superoxide inhibited the formation of ceramide and apoptosis in these cells exposed to nitric oxide probably due to peroxynitrite formation... 

Kinnunen PKJ, Holopainen JM. Sphingomyelinase activity of LDL A link between atherosclerosis, ceramide, and apoptosis ... 

Given the intimate nature of the relationship between ceramide and apoptosis, understanding the mechanisms of ceramide generation and the regulation of its downstream targets in the development and treatment of cancer has become a topic of great interest. 

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. 

This ceramide-mediated apoptosis was shown to be inhibited by the simultaneous addition of PKC activators (Ni et at, 1994 Obeid et al, 1993), implying that PS may activate the ceramide-mediated apoptotic pathway. However, the inhibitors of interleukin-1 converting enzyme (ICE)-like proteases (Caspase), such as tosyl-L-lysine chloromethyl ketone (TLCK), and tosyl-L-phenylalanine chloromethyl ketone (TPCK) which inhibit ceramide-mediated apoptosis, had no effect on PS-induced apoptosis (Figure 4). Thus, PS-induced apoptotic pathway appears to be distinct from that mediated by ceramide. Further studies are required to clarify the molecular mechanisms underlying the PS-induced apoptosis. 

Monney, L., Ohvier, R., Otter, 1., Jansen, B., Poirier, GG., and Bomer, C., 1998, Role ofan acidic compartment in tumor-necrosis-factor-a-induced production of ceramide, activation of caspase-3 and apoptosis. Eur. J. Biochem. 251 295-303 Morrison, H., Jemstrom, B., Nordenskjdld, M., Thor, H., and Orrenius, S., 1984, Induction of DNA damage by menadione (2-methyl-l,4-naphthoquinone) in primary cultures of rat hepatocytes. Biochem. Pharmacol. 33 1763-1769 Neuzil, J., Svensson, 1., Weber, T, Weber, C., and Brunk, U.T., 1999, alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation. FEES Lett. 445 295-300 Ngo, E.O., Nutter, L.M., Sura, T., and Gutierrez, P. L., 1998, Induction ofp53 by the... 

Kroesen, B., Pettus, B., Luberto, C., Busman, M., Sietsma, H., De Leij, L., and Hannun, Y.A., 2001, Induction of apoptosis through B-ceU receptor crosslinking occurs via de novo generated C16 ceramide and involves mitochondria. J. Biol. Chem. pubhshed January 17, 2001 as 10.1074/jbc.M009517200. 

Deaeased PC and PE synthesis by ceramides in combination with the observations that inhibition of PC synthesis induces apoptosis, suggests that in some cell types the effect of ceramides on apoptosis may be exerted at least in part via a disturbance in PC synthesis (see also Section 3). 

Treatment of Rat-2 fibroblasts with various cell-permeable ceramides resulted, as discussed above, in a rapid inhibition of phospholipid synthesis. An intriguing observation was that C2-ceramides inhibited PC biosynthesis without affecting the synthesis of PE via the CDP-ethanolamine route. C2-ceramide are well known inducers of apoptosis and inhibit DNA- and protein synthesis (Obeid et al, 1993 Jayadev et al, 1995). C2-ceramide induced apoptosis in the rat-2 fibroblasts (Houweling et al, unpublished data), suggesting that inhibition of PE biosynthesis is not a prerequisite for apoptosis. 

A recent report suggests that inhibition of PC synthesis constitutes one of the primary events by which C2-ceramide triggers apoptosis (Ramos et al, 2000). Treatment of cerebral granule neurons with C2-ceramide resulted in a rapid (within 1 hour) reduction in PC biosynthesis, whereas only 6 h after exposure to the agonists the first significant drop in cell viability was observed. The authors further showed that addition of exogenous PC resulted in a dose-dependent full prevention of neuronal death. This was specific for PC, because addition of other glycerohpids Uke, PE, PS, phosphatidylinositol and phosphatidic acid had no effect on C2-ceramide-induced apoptosis. 

One of the first reports showing that DAG attenuates ceramide induced apoptosis used two human myeloid leukemia cell lines, namely HL-60 and U937. Exposure of HL-60 and U937 cells to SMase or lOpM ceU-permeable ceramides for 6 h resulted in DNA-laddering, a typical hallmark of apoptosis. This could be aboUshed by di-octanoylglycerol, a cell permeable... 

SMase activity (Mansat et al 1997) and downstream (by blocking the apoptotic effect of ceramide). However, the cross-talk between ceramides and DAG opens new intriguing avenues of research and may lead to better pharmacological maiupulation of key steps in the apoptosis/survival signaling cascade resulting in an increased chemosensitivity of neoplastic cells. 

Allan, D., 2000, Lipid metabolic changes caused by short-chain ceramides and the connection with apoptosis. Biochem. J. 345 603-610... 

Bettaieb, A., Plo, 1., Mansat-de Mas, V., Quillet-Mary, A., Levade, T., Laurent, G., and Jaffrezou, J-P., 1999, Daunorubicin- and Mitoxantrone-tiiggered phosphatidylcholine hydrolysis implication in drug-induced ceramide generation and apoptosis. Mol. Pharm. 55 118-125... 

Yen, C.L., Mar, M.H., and Zeisel, S.H., 1999, Chohne dehdency-induced apoptosis in PC12 ceUs is associated with diminished membrane phosphatidylcholine and sphingomyelin, accumulation of ceramide and diacylglycetol, and achvation of a caspase. FASEB. J. 13 135-142... 

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. 

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... 

CuvUlier, O., Rosenthal, D.S., Smulson, M.E. and Spiegel, S., 1998, Sphingosine 1-phosphate inhibits activation ofcaspases that cleave poly(ADP-ribose)polymerase and lamins during Fas- and ceramide-mediated apoptosis injurkat T lymphocytes,/. Biol. Chem. 273 2910-2916. 

Figure 1. Ceramide mediated apoptosis signaling, Recent investigations hypothesize that, at least for drug induced apoptosis, the src kinase Lyn is activated and recruited to plasma membrane rafts. There it binds to and activates a neutral sphingomyelinase (SMase) within minutes. This initial rise in ceramide levels initiates an apoptotic cascade. Howevo- several cellular events can inhibit ceramide production (by blocking sphingomyelinase activation or clearing out ceramide accumulation through increased metabolisation) and therefore contribute to cellular resistance/survival.

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