Ceramide induced apoptosis

Mizushima, N., Koike, R., Kohsaka, H., Kushi, Y., Handa S., Yagita, H., Miyasaka, N., 1996, Ceramide induces apoptosis via CPP32 activation. FEES Lett. 395 267-271. 

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 C2-ceramide induced apoptosis in the rat-2 fibroblasts (Houweling et al, unpublished data), suggesting that inhibition of PE biosynthesis is not a prerequisite for apoptosis.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... 

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... 

Gomez del Pulgar T, de CebaUos ML, Guzman M, Velasco G (2002a) Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 277 36527-36533... 

Hearps, A.C., Burrows, J., Connor, C.E., Woods, G.M., Lowenthal, R.M., and Ragg, S.J. (2002). Mitochondrial cytochrome c release precedes transmembrane depolarisation and caspase-3 activation during ceramide-induced apoptosis of Jurkat T cells. Apoptosis 7, 387-94. 

Susin SA, Zamzami N, Castedo M, Daugas E, Wang H-G, Geley S, Fassy F, Reed JC, Kroemer G (1997) The central executioner of apoptosis multiple connections between protease activation and mitochondria in Fas/APO-l/CD95- and ceramide-induced apoptosis. J Exp Med 186 25-37... 

Other novel structural analogs of ceramide, such as Cig-serinol and (2S,3R)-(4E,6E)-2-octanoylamidooctadecadiene-l,3-diol (4,6-diene-ceramide) induced apoptosis in various human cancer cells (Bieberich et al., 2000 Struckhoff et al.,... 

Stover, T. and Kester, M. Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells. J Pharmacol Exp Ther, 307, 2003, 468-475. 

Taken together, ASMase appears to be important in endotoxemia based on its involvement in ceramide-induced apoptosis in contrast, any solid evidence for a role of the enzyme in inflammatory responses is not available. 

Kolesnick, R., and Fuks, Z., Radiation and ceramide-induced apoptosis. Oncogene, 22 (2003) 5897-5906. 

One downstream effector for ceramide-induced apoptosis may be the retinoblastoma protein (Rb). Serum withdrawal induced cell cycle arrest and dephosphorylation of Rb in MOLT-4 cells associated with increased levels of endogenous cera-mide, whereas sphingosine levels were unaffected. Addition of exogenous ceramide also induced dephosphorylation of Rb in these cells. Ceramide did not induce cell cycle arrest in cells that had defective or inactive Rb (Dbaibo et al., 1995). These data are consistent with the current models of Rb action, in which hypophosphorylation of Rb protein correlates with its ability to bind to transcription factors such as those of of the E2F family and to repress progression through the G1 phase of the cell cycle (Ewen, 1994). 

Fig. 7.9 Generation of JV-acylethanolamine (NAE) and A-acylphosphatidylethanolamine (NAPE) in brain. Phosphatidylcholine (PtdCho) phosphatidylethanolamine (PtdEtn) cannabinoid lecep-torl (CBj-R) JV-methyl-D-aspartate receptor (NMDA-R) tmandamide and 2-arachidonyl-gltcerol not only stimulate CBi-R but also have stabilizing effects on neural membranes. TBI increases the formation of NAE and NAPE. Ai-arachidonylethanolamine stimulate ceramide formation, N-acylethanolamine inhibit ceramidase. Ceramide induces apoptosis. Plus sign indicate stimulation and minus sign indicates inhibition, (f) Indicate increase in levels...

Herget, T., Esdar, C., Oehrlein, S.A., Heinrich, M., Schutze, S., Maelicke, A., and van Echten-Deckert, G. (2000) Production of Ceramides Causes Apoptosis During Early Neural Differentiation In Vitro, J. Biol. Chem. 275, 30344—30354. Willaime, S., Vanhoutte, P., Caboche, J., Lemaigre-Dubreuil, Y, Mariani, J., and Brugg, B. (2001) Ceramide-Induced Apoptosis in Cortical Neurons Is Mediated by an Increase in p38 Phosphorylation and Not by the Decrease in ERK Phosphorylation, Eur. J. Neurosci. 13,2037-2046. 

Sugiki, H., Hozumi, Y., Maeshima, H., Katagata, Y., Mit-suhashi, Y, and Kondo, S. (2000) C2-Ceramide Induces Apoptosis in a Human Squamous CeU Carcinoma Cell Line, Br. J. Dermatol. 143,1154-1163. 

The different effects of CGs on human tumor compared to normal cells are observed. For instance, oleandrin inhibits the activation of certain transcription factors and potentiates ceramide-induced apoptosis in human tumor cells rather than in normal, primary human cells [11]. Researchers also [12] indicate that CGs sensitize human tumor but not normal cells to subsequent radiation treatment. These data suggest that it may be possible to exploit differences in the Na /K ATPase pumps of normal as opposed to tumor cells to improve the therapeutic index of radiation therapy. 

Bragg, B, Michel, PP, Agid, Y andRuberg, M (1996) Ceramide induces apoptosis in cultured mesencephalic neurons. JNeurochem, 66, 733-739. 

Kondo, T, Kitano, T, Iwai, K, Watanabe, M, Taguchi, Y, Yabu, T, Umehara, H, Domae, N, Uchiyama, T and Okazaki, T (2002) Control of ceramide-induced apoptosis by IGF-1 involvement of PI-3 kinase, caspase-3 and catalase. Cell Death Dijfer, 9, 682-692. 

Pelled, D, Raveh, T, Riebehng, C, Fridkin, M, Berissi, H, Futerman, AH and Kimchi, A (2002) Death-associated protein (DAP) kinase plays a central role in ceramide-induced apoptosis in cultured hippocampal neurons. J Biol Chem, Til, 1957-1961. 

Radin, NS (2003) Killing tumours by ceramide-induced apoptosis a critique of available... 

Certain natural compounds possess anti-apoptotic effects. For example, ascorbic acid and a-tocopherol prevent apoptosis caused by serum withdrawal in HL-60 cells with the antioxidative effects (76). Caffeic acid inhibits ceramide-induced apoptosis in U937 cells through the inhibition of protein tyrosine kinase activity 17). Quercetin inhibits hydrogen peroxide-induced apoptosis via intervention in the activator protein 1 (AP-1) -mediated apoptotic pathway 18). Epigallocatechin-3-gallate and theaflavins inhibits arsenite-induced apoptosis through the decrease in phosphorylation of Erks and JNKs (79). Therefore, it is important to know whether these natural compounds show inhibitory effects on Trp-P-1-induced apoptosis. In this study, we demonstrated that Trp-P-1 induced caspase-8-initiated apoptosis in rat MNCs, and that certain food components inhibited Trp-P-l-induced apoptosis. 

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