Regulation of Cell Death/Survival by Ceramide and Sphingosin-1-Phosphate
	Ceramide is a major sphingolipid with sphingosine as its basic structure. We reported in 1989 that ceramide increased intracellularly during the growth inhibition period in cell differentiation, and exogenous cell-permeable synthetic ceramide is known to induce cell differentiation.1),2) Since then, ceramide has been further recognized as a signal-transducing molecule in cell death and survival. Ceramide is degraded with ceramidase to sphingosine, which is then phosphorylated by sphingosine kinase to form sphingosine-1-phosphate (S1P).3) The chemotactic effect of S1P and its platelet aggregation action induced by its release from platelets were reported for the first time by Igarashi et al.,4) and the association with fibroblast proliferation and calcium increase were reported by Spiegel et al..5) S1P is attracting more attention for its intracellular signaling functioning in cell survival and during cell growth, rather than simply as an intracellular. The amount of ceramide within cells is regulated by intracellular production and degradation, which is induced by various stresses and controlled by ceramide-associated enzymes such as sphigomyelinase (SMase), ceramidase, glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS), as shown in Fig. 1. On the other hand, S1P degradation is regulated by S1P lyase and phosphoproteinphosphatase. Intracellular ceramide induces the capase family and reactive oxygen intermediates (ROI), which are signals for inducing apoptosis, whereas S1P is known to extracellularly activate the phosphatidylinositol 3-kinase (PI-3) pathway through G-protein-binding endothelial differentiation gene (EDG) family receptors.4) The interaction of ceramide with S1P on cell function was reported in 1996, i.e., S1P enhances the activation of protein kinase C, which leads to the inhibition of ceramide-induced apoptosis.6) Our studies showed that ceramide-induced apoptosis is activated via inhibition of PI-3 activity/ Akt kinase activity, and that PI-3 potentiates inhibition of sphigomyelinase (SMase) activity and subsequently inhibits the ability to produce intracellular ceramide in response to stress,7),8) as shown in Fig. 2. Furthermore, recent findings identified the EDG family as the receptors for S1P intercellular reaction and also showed that PI-3 activity, which is induced via G-protein-binding phospholipase C activation, to be an important factor in the S1P downstream signal. These findings suggest that PI-3 may play an important role in controlling the interaction signal of ceramide and S1P.8) In addition, preliminary studies show that ceramide binds to and regulates directly PI-3 intracellularly and that ceramide may control the cell proliferation signals downstream.9) From the above, sphingolipid, ceramide and S1P function interdependently and are deeply correlated with cell proliferation, cell survival and induction of apoptosis.5) Their interaction in the mechanism of maintaining a microdomain structure on the cell membrane is also becoming a subject of recent interest.10)
	Fig. 1 Ceramide Metabolism
	Fig. 2 Correlation between pro-apoptotic ceramide and pro-survival sphingosine-1-phosphate signaling
	Toshiro Okazaki (Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University)
	References (1) Okazaki T, Kondo T, Kitano T, Tashima M: Diversity and complexity of ceramide signalling in apoptosis. Cell Signal. 10, 685-692, 1998 (2) Obeid LM, Hannun YA: Ceramide, stress, and a "LAG" in aging. Sci Aging Knowledge Environ. PE27, 2003 (3) Spiegel S, Milstien S: Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 4, 397-407, 2003 (4) Igarashi Y: Current studies on a novel lipid mediator, sphingosine 1-phosphate, and its receptors. Tanpakushitsu Kakusan Koso, 47, 476-479, 2002 (5) Perry DK, Kolesnick RN: Ceramide and sphingosine 1-phosphate in anti-cancer therapies. Cancer Treat Res. 115, 345-354, 2003 (6) Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind S, Spiegel S: Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 381, 800-803, 1996 (7) Kondo T, Kitano T, Iwai K, Watanabe M, Taguchi Y, Yabu T, Umehara H, Domae N, Uchiyama T, Okazaki T: Control of ceramide-induced apoptosis by IGF-1: involvement of PI-3 kinase, caspase-3 and catalase. Cell Death Differ. 9, 682-692, 2002 (8) Kondo T, Okazaki T: Crosstalk between ceramide and phosphatidylinositol-3 kinase as a mechanism for cell death/survival determination. Tanpakushitsu Kakusan Koso, 47, 442-448, 2002 (9) Okazaki T, Ito M: Signal transduction of ceramide. Tanpakushitsu Kakusan Koso, 47, 438-441, 2002 (10) Gulbins E, Kolesnick R: Raft ceramide in molecular medicine. Oncogene, 22, 7070-7077, 2003
Jul. 6, 2004