Altering the sphingosine-1-phosphate/ceramide balance: A promising approach for tumor therapy

Current Pharmaceutical Design

Volumn 12, Issue 35, 2006, Pages 4625-4635

  Huwiler, Andrea ^a   Pfeilschifter, Josef ^a  

^a UNIVERSITY HOSPITAL FRANKFURT   (Germany)

Author keywords

Angiogenesis; Apoptosis; Cell proliferation; Ceramide; FTY720; Protein kinase B; Sphinganine

Indexed keywords

2 (3,4 DIHYDROXYBENZYLIDENE) BENZOFURAN 3 ONE; 5 (2,4 DIHYDROXYBENZYLIDENE) 3 (4 METHOXYPHENYL) 2 THIOXO THIAZOLIDINE 4 ONE); ACYLSPHINGOSINE DEACYLASE; B 13; CERAMIDASE INHIBITOR; CERAMIDE; CYCLOSPORIN A; DEXTRO ERYTHRO 2 N MYRISTOYLAMINO 1 NITROPHENYL PROPAN 1,2 DIOL; DEXTRO ERYTHRO 2 N MYSRISTOYLAMINO 1 PHENYL 1 PROPANOL; ENZYME INHIBITOR; FINGOLIMOD; FINGOLIMOD PHOSPHATE; IMMUNOSUPPRESSIVE AGENT; JTE 013; N,N DIMETHYLSPHINGOSINE; RECEPTOR BLOCKING AGENT; SAFINGOL; SPHINGOSINE 1 PHOSPHATE; SPHINGOSINE 1 PHOSPHATE RECEPTOR; SPHINGOSINE 1 PHOSPHATE RECEPTOR ANTAGONIST; SPHINGOSINE KINASE; SPHINGOSINE KINASE INHIBITOR; THERMOZYMOCIDIN;

APOPTOSIS; CANCER THERAPY; CARCINOGENESIS; CELL DEATH; CELL PROLIFERATION; CELL TYPE; DRUG STRUCTURE; DRUG TARGETING; ENZYME INHIBITION; HUMAN; INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; RECEPTOR BINDING; REVIEW; SIGNAL TRANSDUCTION;

AMIDOHYDROLASES; ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL MOVEMENT; CELL PROLIFERATION; CERAMIDES; ENZYME INHIBITORS; HUMANS; LIPID METABOLISM; LYSOPHOSPHOLIPIDS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PHOSPHOTRANSFERASES (ALCOHOL GROUP ACCEPTOR); PROPYLENE GLYCOLS; RECEPTORS, LYSOSPHINGOLIPID; SIGNAL TRANSDUCTION; SPHINGOSINE;

EID: 33751541195     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161206779010422     Document Type: Review

References (155)

1. Berridge MJ. Inositol trisphosphate and diacylglycerol as second messengers. Biochem J 1984; 220: 345-60.
2. Rhee SG, Suh PG, Ryu SH, Lee SY. Studies of inositol phospholipid-specific phospholipase C. Science 1989; 244:546-50.
3. Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 1995; 9:484-96.
4. Serhan CN, Haeggstrom JZ, Leslie CC. Lipid mediator networks in cell signaling: update and impact of cytokines. FASEB J 1996; 10: 1147-58.
5. Linn SC, Kim, HS, Keane EM, Andrai LM, Wang E, Merrill AH Jr. Regulation of de novo sphingolipid biosynthesis and the toxic consequences of its disruption. Biochem Soc Trans 2001; 29: 831-5.
6. Xu Y, Xiao YJ, Baudhuin LM, Lu J, Hong G, Kim KS, et al. Unfolding the pathophysiological role of bioactive lysophospholipids. Curr. Drug Targets Immune Endocr Metabol Disord 2003; 3: 23-32.
7. Huwiler A, Kolter T, Pfeilschifter J, Sandhoff K. Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim Biophys Acta 2000; 1485: 63-99.
8. Sandhoff K, Kolter T, van Echten-Deckert G. Sphingolipid metabolism. Sphingoid analogs, sphingolipid activator proteins, and the pathology of the cell. Ann N Y Acad Sci 1998; 845: 139-51.
9. Riboni L, Viani P, Bassi R, Prinetti A, Tettamanti G. The role of sphingolipids in the process of signal transduction. Prog Lipid Res 1997; 36: 153-95.
10. Hannun YA, Loomis CR, Merrill AH Jr, Bell RM. Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J Biol Chem 1986; 261: 12604-9.
11. Hannun YA, Bell RM. Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 1987; 235: 670-4.
12. Quintern LE, Schuchman EH, Levran O, Suchi M, Ferlinz K, Reinke H, et al. Isolation of cDNA clones encoding human acid sphingomyelinase: occurrence of alternatively processed transcripts. EMBO J 1989; 8: 2469-73.
13. Levade T, Jaffrezou JP. Signalling sphingomyelinases: which, where, how and why? Biochim Biophys Acta 1999; 1438: 1-17.
14. Bose R, Verheij M, Haimovitz-Friedman A, Scotto K, Fuks Z, Kolesnick R. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 1995; 82: 405-14.
15. Shimeno H, Soeda S, Sakamoto M, Kouchi T, Kowakame T, Kihara T. Partial purification and characterization of sphingosine N-acyltransferase (ceramide synthase) from bovine liver mitochondrion-rich fraction. Lipids 1998; 33: 601-5.
16. Pettus BJ, Chalfant CE, Hannun YA. Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta 2002; 1585: 114-25.
17. Kolesnick RN, Goni FM, Alonso A. Compartmentalization of ceramide signaling: physical foundations and biological effects. J Cell Physiol 2000; 184: 285-300.
18. Stoffel W, Heimann G, Hellenbroich B. Sphingosine kinase in blood platelets. Hoppe Seylers Z Physiol Chem 1973; 354: 562-6.
19. Kohama T, Olivera A, Edsall L, Nagiec MM, Dickson R, Spiegel S. Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem 1998; 273: 23722-8.
20. Liu H, Sugiura M, Nava VE, Edsall LC, Kono K, Poulton S, et al. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem 2000; 275: 19513-20.
21. Olivera A, Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 1993; 365: 557-60.
22. Shu X, Wu W, Mosteller RD, Broek D. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol Cell Biol 2002; 22: 7758-68.
23. Rius RA, Edsall LC, Spiegel S. Activation of sphingosine kinase in pheochromocytoma PC12 neuronal cells in response to trophic factors. FEBS Lett 1997; 417: 173-76.
24. Meyer zu Heringdorf D, Lass H, Kuchar I, Alemany R, Guo Y, Schmidt M, Jakobs KH. Role of sphingosine kinase in Ca(2+) signalling by epidermal growth factor receptor. FEBS Lett 1999; 461: 217-22.
25. Alemany R, Sichelschmidt B, Zu Heringdorf DM, Lass H, van Koppen CJ, Jakobs KH. Stimulation of sphingosine-1-phosphate formation by the P2Y(2) receptor in HL-60 cells: Ca(2+) requirement and implication in receptor-mediated Ca(2+) mobilization, but not MAP kinase activation. Mol Pharmacol 2000; 58: 491-7.
26. Mazurek N, Megedish T, Hakomori S, Igarashi Y. Regulatory effect of phorbol esters on sphingosine kinase in BALB/C 3T3 fibroblasts (variant A31): demonstration of cell type-specific response - a preliminary note. Biochem Biophys Res Commun 1994; 198: 1-9.
27. Auge N, Nikolova-Karakashian M, Carpentier S, Parthasarathy S, Negre-Salvayre A, Salvayre R, et al. Role of sphingosine 1-phosphate in the mitogenesis induced by oxidized low density lipoprotein in smooth muscle cells via activation of sphingomyelinase, ceramidase, and sphingosine kinase. J Biol Chem 1999; 274: 21533-8.
28. Xia P, Gamble JR, Rye KA, Wang L, Hii CS, Cockerill P, et al. Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway. Proc Natl Acad Sci USA 1998; 95: 14196-201.
29. Pitson SM, Moretti PA, Zebol JR, Lynn HE, Xia P, Vadas MA, et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J 2003; 22: 5491-500.
30. Van Veldhoven PP, Mannaerts GP. Subcellular localization and membrane topology of sphingosine-1-phosphate lyase in rat liver. J Biol Chem 1991; 266: 12502-7.
31. LeStunff H, Peterson C, Thornton R, Milstien S, Spiegel S. Characterization of murine sphingosine-1-phosphate phosphohydrolase. J Biol Chem 2002; 277: 8920-7.
32. Mandala SM, Thornton R, Galve-Roperth I, Poulton S, Peterson C, Olivera A, et al. Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine-1- phosphate and induces cell death.Proc Natl Acad Sci USA 2000; 97: 7859-64.
33. Zhou J, Saba JD. Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast. Biochem Biophys Res Commun 1998; 242: 502-7.
34. Yatomi Y, Igarashi Y, Yang L, Hisano N, Qi R, Asazuma N, et al. Sphingosine-1-phosphate, a bioactive sphingolipid abundantly stored in platelets, is a normal constituent of human plasma and serum. J Biochem 1997; 121: 969-73.
35. Reiss U, Oskouian B, Zhou J, Gupta V, Sooriyakumaran P, Kelly S, et al. Sphingosine-phosphate lyase enhances stress-induced ceramide generation and apoptosis. J Biol Chem 2004; 279: 1281-90.
36. Pettus BJ, Bielawski J, Porcelli AM, Reames DL, Johnson KR, Morrow J, et al. The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha. FASEB J 2003; 17: 1411-21.
37. Herr DR, Fyrst H, Phan V, Heeinecke K, Georges R, Harris GL, et al. Sply regulation of sphingolipid signaling molecules is essential for Drosophila development. Development 2003; 130: 2443-2453.
38. Mendel J, Heinecke K, Fyrst H, Saba JD. Sphingosine phosphate lyase expression is essential for normal development in Caenorhabditis elegans. J Biol Chem 2003; 278: 22341-9.
39. Lee M, Van Brocklyn JR, Thangada S, Liu CH, Hand AR, Menzeleey R, et al. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1.Science 1998; 279: 1552-5.
40. Zondag GC, Postma FR, Etten IV, Verlaan I, Moolenaar WH. Sphingosine 1-phosphate signalling through the G-protein-coupled receptor Edg-1. Biochem J 1998;330:605-9.
41. Hla T, Maciag T. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. J Biol Chem 1990; 265: 9308-13.
42. Goetzl EJ, An S. Diversity of cellular receptors and functions for the lysophospholipid growth factors lysophosphatidic acid and sphingosine 1-phosphate. FASEB J 1998; 12: 1589-98.
43. Graler MH, Bernhardt G, Lipp M. EDG6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue. Genomics 1998; 53: 164-9.
44. Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W, et al. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev 2002; 54: 265-69.
45. Ammit AJ, Hastie AT, Edsall LC, Hoffman RK, Amrani Y, Krymskaya VP, et al. Sphingosine-1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma. FASEB J 2001; 15: 1212-4.
46. van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel AH, Borst P, et al. MDR1 P-glycoprotein is a translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 1996; 87: 507-17.
47. Raggers RJ, Pomorski T, Holthuis JCM, Kalin N, van Meer G. Lipid traffic: the ABC of transbilayer movement. Traffic 2000; 1: 226-34.
48. Raggers RJ, van Helvoort A, Evers R, van Meer G. The human multidrug resistance protein MRP1 translocates sphingolipid analogs across the plasma membrane.J Cell Sci 1999; 112: 415-22.
49. Boujaoude LC, Bradshaw-Wilder C, Mao C, Cohn J, Ogretmen B, Hannun YA, et al. Cystic fibrosis transmembrane regulator regulates uptake of sphingoid base phosphates and lysophosphatidic acid: modulation of cellular activity of sphingosine 1-phosphate. J Biol Chem 2001; 276: 35258-64.
50. Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Med 2003; 4: 397-406.
51. Hla T. Signaling and biological actions of sphingosine-1-phosphate. Pharmacol Res 2003; 47: 401-7.
52. Van Brocklyn JR, Lee MJ, Menzeleev R, Olivera A, Edsall L, Cuvillier O, et al. Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled receptor Edg-1 and intracellular to regulate proliferation and survival. J Cell Biol 1998; 142: 229-40.
53. Skrzypek M S, Nagiec MM, Lester RL, Dickson RC. Analysis of phosphorylated sphingolipid long-chain bases reveals potential roles in heat stress and growth control in Saccharomyces. J Bacteriol 1999; 181: 1134 -40.
54. Postma FR, Jalink K, Hengeveld T, Moolenaar WH. Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action through a specific cell surface receptor. EMBO J 1996; 15: 2388-92.
55. Vogler R, Sauer B, Kim DS, Schafer-Korting M, Kleuser B. Sphingosine-1-phosphate and its potentially paradoxical effects on critical parameters of cutaneous wound healing. J Invest Dermatol 2003; 120: 693-700.
56. Qiao L, Kozikowski AP, Olivera A, Spiegel S. Synthesis and evaluation of a photolyzable derivative of sphingosine 1-phosphate - caged SPP. Bioorg Med Chem Lett 1998; 8: 711-4.
57. Meyer ZU, Heringdorf D, Liliom K, Schaefer M, Danneberg K, Jaggar JH, et al. Photolysis of intracellular caged sphingosine-1-phosphate causes Ca2+ mobilization independently of G-proteincoupled receptors. FEBS Lett 2003; 554: 443-9.
58. Merrill AH Jr, Schmelz EM, Dillehay DL, Spiegel S, Shayman JA, Schroeder JJ, et al. Sphingolipids - the enigmatic lipid class: biochemistry, physiology, and pathophysiology. Toxicol Appl Pharmacol 1997; 142: 208-25.
59. Wakita H, Tokura Y, Yagi H, Nishimura K, Furukawa F, Takigawa M. Keratinocyte differentiation is induced by cell-permeant ceramides and its proliferation is promoted by sphingosine. Arch Dermatol Res 1994; 286: 350-4.
60. Olivera A, Zhang H, Carlson RO, Mattie ME, Schmidt RR, Spiegel S. Stereospecificity of sphingosine-induced intracellular calcium mobilization and cellular proliferation. J Biol Chem 1994; 269: 17924-30.
61. Hauser JM, Buehrer BM, Bell RM. Role of ceramide in mitogenesis induced by exogenous sphingoid bases. J Biol Chem 1994; 269: 6803-9.
62. Jarvis WD, Fornari FA Jr, Auer KL, Freemerman AJ, Szabo E, Birrer MJ, et al. Coordinate regulation of stress- and mitogen-activated protein kinases in the apoptotic actions of ceramide and sphingosine. Mol Pharmacol 1997; 52: 935-47.
63. Hung WC, Chang HC, Chuang LY. Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells. Biochem J 1999; 338: 161-6.
64. Sakakura C, Sweeney EA, Shirahama T, Hagiwara A, Yamaguchi T, Takahashi T, et al. Selectivity of sphingosine-induced apoptosis. Lack of activity of DL-erythro-dihydrosphingosine. Biochem Biophys Res Commun 1998; 246: 827-30.
65. Cuvillier O. Sphingosine in apoptosis signaling. Biochim Biophys Acta 2002; 1585: 153-62.
66. Titievsky A, Titievskaya I, Pasternack M, Kaila K, Tornquist K. Sphingosine inhibits voltage-operated calcium channels in GH4C1 cells. J Biol Chem 1998; 273: 242-7.
67. Mathes C, Fleig A, Penner R. Calcium release-activated calcium current (ICRAC) is a direct target for sphingosine. J Biol Chem 1998; 273: 25020-30.
68. Jefferson AB, Schulman H. Sphingosine inhibits calmodulindependent enzymes. J Biol Chem 1988; 263: 15241-4.
69. Arnold RS, Newton AC. Inhibition of the insulin receptor tyrosine kinase by sphingosine. Biochemistry 1991; 30: 7747-54.
70. Yamada K, Sakane F, Imai S, Takemura H. Sphingosine activates cellular diacylglycerol kinase in intact Jurkat cells, a human T-cell line. Biochim Biophys Acta 1993; 1169: 217-24.
71. McDonald OB, Hannun YA, Reynolds CH, Sahyoun N. Activation of casein kinase II by sphingosine. J Biol Chem 1991; 266: 21773-6.
72. Megidish T, White T, Takio K, Titani K, Igarashi Y, Hakomori S. The signal modulator protein 14-3-3 is a target of sphingosine- or N, N-dimethylsphingosine-dependent kinase in 3T3(A31) cells. Biochem Biophys Res Commun 1995; 216: 739-47.
73. Megidish T, Cooper J, Zhang L, Fu H, Hakomori S. A novel sphingosine-dependent protein kinase (SDK1) specifically phosphorylates certain isoforms of 14-3-3 protein. J Biol Chem 1998; 273: 21834-45.
74. Megidish T, Takio K, Titani K, Iwabuchi K, Hamaguchi A, Igarashi Y, et al. Endogenous substrates of sphingosine-dependent kinases (SDKs) are chaperone proteins: heat shock proteins, glucose-regulated proteins, protein disulfide isomerase, and calreticulin. Biochemistry 1999; 38: 3369-78.
75. Raines MA, Kolesnick RN, Golde DW. Sphingomyelinase and ceramide activate mitogen-activated protein kinase in myeloid HL-60 cells.J Biol Chem 1993; 268: 14572-5.
76. Huwiler A, Brunner J, Hummel R, Vervoordeldonk M, Stabel S, van den Bosch H, et al. Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase. Proc Natl Acad Sci USA 1996; 93: 6959-63.
77. Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, et al. Fuks Z, Kolesnick RN. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis.Nature 1996; 380: 75-9.
78. Weber T, Brunner J. 2-(tributylstannyl)-4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzyl alcohol: a building block for photolabeling and cross-linking reagents of very high specific radioactivity. J Am Chem Soc 1995; 117: 3084-95.
79. Brunner J. Use of photocrosslinkers in cell biology. Trends Cell Biol 1996; 6: 154-7.
80. Heinrich M, Wickel M, Schneider-Brachert W, Sandberg C, Gahr J, Schwandner R, et al. Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J. 1999; 18: 5252-63.
81. Hekman M, Hamm H, Villar AV, bader B, Kuhlmann J, Nickel J, Rapp UR. Associations of B- and C-Raf with cholesterol, phosphatidylserine, and lipid second messengers: preferential binding of Raf to artificial lipid rafts. J Biol Chem 2002; 277: 24090-102.
82. Müller G, Storz P, Bourteele S, Doppler H, Pfizenmaier K, Mischak H, et al. Regulation of Raf-1 kinase by TNF via its second messenger ceramide and cross-talk with mitogenic signalling. EMBO J 1998; 17: 732-42.
83. Zhou M, Horita DA, Waugh DS, Byrd RA, Morrison DK. Solution structure and functional analysis of the cysteine-rich C1 domain of kinase suppressor of Ras (KSR). J Mol Biol 2002; 315: 435-46.
84. Huwiler A, Xin C, Brust AK, Briner VA, Pfeilschifter J. Differential binding of ceramide to MEKK1 in glomerular endothelial and mesangial cells. Biochim Biophys Acta 2004; 1636: 159-68.
85. Huwiler A, Fabbro D, Pfeilschifter J. Selective ceramide binding to protein kinase C-α and -δ isoenzymes in renal mesangial cells. Biochemistry 1998; 37: 14556-62.
86. Müller G, Ayoub M, Storz P, Rennecke J, Fabbro D, Pfizenmaier K. PKC zeta is a molecular switch in signal transduction of TNF-alpha, bifunctionally regulated by ceramide and arachidonic acid. EMBO J 1995; 14: 1961-69.
87. Huwiler A, Johansen B, Skarstad A, Pfeilschifter J. Ceramide binds to the CaLB domain of cytosolic phospholipase A2 and facilitates its membrane docking and arachidonic acid release. FASEB J 2001; 15: 7-9.
88. Mizushima N, Koike R, Kohsaka H, Kushi Y, Handa S, Yagita H, et al. Ceramide induces apoptosis via CPP32 activation. FEBS Lett 1996; 395: 267-71.
89. Tepper AD, Cock JG, de Vries E, Borst J, van Blitterswijk WJ. CD95/ Fas-induced ceramide formation proceeds with slow kinetics and is not blocked by caspase-3/CPP32 inhibition. J Biol Chem 1997; 272: 24308-12.
90. Spinedi A, Amendola A, Di Bartolomeo S, Piacentini M. Ceramide-induced apoptosis is mediated by caspase activation independently from retinoblastoma protein post-translational modification. Biochem Biophys Res Commun 1998; 243: 852-7.
91. Gamen S, Marzo I, Anel A, Pineiro A, Naval J. CPP32 inhibition prevents Fas-induced ceramide generation and apoptosis in human cells. FEBS Lett 1996; 390: 232-7.
92. Takeda Y, Tashima M, Takahashi A, Uchiyama T, Okazaki T. Ceramide generation in nitric oxide-induced apoptosis. Activation of magnesium-dependent neutral sphingomyelinase via caspase-3. J Biol Chem 1999; 274: 10654-60.
93. Brenner B, Ferlinz K, Grassme H, Weller M, Koppenhoefer U, Dichgans J, et al. Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases. Cell Death Diff 1998; 5: 29-37.
94. Tepper AD, de Vries E, van Blitterswijk WJ, Borst J. Ordering of ceramide formation, caspase activation, and mitochondrial changes during CD95- and DNA damage-induced apoptosis. J Clin Invest 1999; 103: 971-8.
95. Nicotera P, Leist M, Manzo L. Neuronal cell death: a demise with different shapes. Trends Pharmacol Sci 1999; 20: 46-51.
96. Obeid LM, Linardic CM, Karolak LA, Hannun YA. Programmed cell death induced by ceramide. Science 1993; 259: 1769-71.
97. Salinas M, Lopez-Valdaliso R, Martin D, Alvarez A, Cuadrado A. Inhibition of PKB/Akt1 by C2-ceramide involves activation of ceramide-activated protein phosphatase in PC12 cells. Mol Cell Neurosci 2000; 15: 156-69.
98. Schubert KM, Scheid MP, Duronio V. Ceramide inhibits protein kinase B/ Akt by promoting dephosphorylation of serine 473. J Biol Chem 2000; 275: 13330-5.
99. Zinda MJ, Vlahos CJ, Lai MT. Ceramide induces the dephosphorylation and inhibition of constitutively activated Akt in PTEN negative U87mg cells. Biochem Biophys Res Commun 2001; 280: 1107-15.
100. Zundel W, Giaccia A. Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress. Genes Develop 1998; 12: 1941-6.
101. Bourbon NA, Sandirasegarane L, Kester M. Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J Biol Chem 2002; 277: 3286-92.
102. Selzner M, Bielawska A, Morse MA, Rüdiger HA, Sindram D, Hannun YA, et al. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res 2001; 61: 1233-40.
103. Quintans J, Kilkus J, McShan CL, Gottschalk AR, Dawson G. Ceramide mediates the apoptotic response of WEHI 231 cells to anti-immunoglobulin, corticosteroids and irradiation. Biochem Biophys Res Commun 1994; 202: 710-4.
104. Mengubas K, Riordan FA, Bravery CA, Lewin J, Owens DL, Mehta AB, et al. Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism. Oncogene 1999; 18: 2499-506.
105. Ahn EH, Schroeder JJ. Sphingoid bases and ceramide induce apoptosis in HT-29 and HCT-116 human colon cancer cells. Exp Biol Med 2002; 227: 345-53.
106. Phillips DC, Allen K, Griffiths HR. Synthetic ceramides induce growth arrest or apoptosis by altering cellular redox status. Arch Biochem Biophys 2002; 407: 15-24.
107. Dagan A, Wang C, Fibach E, Gatt S. Synthetic, non-natural sphingolipid analogs inhibit the biosynthesis of cellular sphingolipids, elevate ceramide and induce apoptotic cell death. Biochim Biophys Acta 2003; 1633: 161-9.
108. Lucci A, Han TY, Liu YY, Giuliano AE, Cabot MC. Multidrug resistance modulators and doxorubicin synergize to elevate ceramide levels and elicit apoptosis in drug-resistant cancer cells. Cancer 1999; 86: 300-11.
109. Charles AG, Han TY, Liu YY, Hansen N, Giuliano AE, Cabot MC. Taxol-induced ceramide generation and apoptosis in human breast cancer cells. Cancer Chemother Pharmacol 2001; 47: 444-50.
110. Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ, Hannun YA. Serinepalmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem 2000; 275: 9078-84.
111. Haimovitz-Friedman A, Kan CC, Ehleiter D, Persaud RS, McLoughlin M, Fuks Z, et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med 1994; 180: 525-35.
112. Jaffrezou JP, Levade T, Bettaieb A, Andrieu N, Bezombes C, Maestre N, et al. Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J 1996; 15: 2417-24.
113. Chauvier D, Moriani H, Manfait M. Ceramide involvement in homocamptothecin- and camptothecin-induced cytotoxicity and apoptosis in colon HT29 cells. Int J Oncol 2002; 20: 855-63.
114. Musumarra G, Barresi V, Condorelli DF, Scire S. A bioinformatic approach to the identification of candidate genes for the development of new cancer diagnostics. Biol Chem 2003; 384: 321-7.
115. Xia P, Wang L, Moretti PAB, Albanese N, Chai F, Pitson SM, et al. Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling. J Biol Chem 2002; 277: 7996-8003.
116. Xia P, Gamble JR, Wang L, Pitson SM, Moretti PA, Wattenberg BW, D'Andrea RJ, Vadas MA. An oncogenic role of sphingosine kinase. Curr Biol 2000; 10: 1527-30.
117. French KJ, Schrencengost RS, Lee BD, Zhuang Y, Smith SN, Eberly JL, et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 2003; 63: 5962-9.
118. Olivera A, Kohama T, Tu Z, Milstien S, Spiegel S. Purification and characterization of rat kidney sphingosine kinase.J Biol Chem 1998; 273: 12576-83.
119. Buehrer BM, Bell RM. Inhibition of sphingosine kinase in vitro and in platelets. Implications for signal transduction pathways. J Biol Chem 1992; 267: 3154-9.
120. Yatomi Y, Ruan F, Megidish T, Toyokuni T, Hakomori S, Igarashi Y. N, N-dimethylsphingosine inhibition of sphingosine kinase and sphingosine 1-phosphate activity in human platelets. Biochemistry 1996; 35: 626-33.
121. Hoffmann TK, Leenen K, Hafner D, Balz V, Gerharz CD, Grund A, et al. Antitumor activity of protein kinase C inhibitors and cisplatin in human head and neck squamous cell carcinoma lines. Anticancer Drugs 2002; 13: 93-100.
122. Schwartz GK, Ward D, Saltz L, Casper ES, Spiess T, Mullen E, et al. A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin.Clin Cancer Res 1997; 3: 537-43.
123. Endo K, Igarashi Y, Nisar M, Zhou OH, Hakomori S. Cell membrane signaling as target in cancer therapy: inhibitory effect of N, N-dimethyl and N, N, N-trimethyl sphingosine derivatives on in vitro and in vivo growth of human tumor cells in nude mice. Cancer Res 1991; 51: 1613-8.
124. Yatomi Y, Ruan F, Megidish T, Toyokuni T, Hakomori S, Igarashi Y. N, N- dimethylsphingosine inhibition of sphingosine kinase and sphingosine 1-phosphate activity in human platelets. Biochemistry 1996; 35: 626-33.
125. Nava VE, Cuvillier O, Edsall LC, Kimura K, Milstien S, Gelmann EP, et al. Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells. Cancer Res 2000; 60: 4468-74.
126. Morita Y, Perez GI, Paris F, Miranda SR, Ehleiter D, Haimovitz-Friedman A, et al. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat Med 2000; 6: 1109-14.
127. Paris F, Perez GI, Fuks Z, Haimovitz-Friedman A, Nguyen H, Bose M, et al. Sphingosine 1-phosphate preserves fertility in irradiated female mice without propagating genomic damage in offspring. Nat Med 2002; 8: 901-2.
128. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29(6 Suppl 16): 15-8.
129. Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis.Recent Prog Horm Res 2000; 55: 15-35.
130. Friesel RE, Maciag T. Molecular mechanisms of angiogenesis: fibroblast growth factor signal transduction. FASEB J 1995; 9: 919-25.
131. Lee OH, Kim YM, Lee YM, Moon EJ, Lee DJ, Kim JH, et al. Sphingosine 1-phosphate induces angiogenesis: its angiogenic action and signaling mechanism in human umbilical vein endothelial cells. Biochem Biophys Res Commun 1999; 264: 743-50.
132. Liu Y, Wada R, Yamashita T, Mi Y, Deng CX, Hobson JP, et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 2000; 106: 951-61.
133. Chae SS, Paik JH, Allende ML, Proia RL, Hla T. Regulation of limb development by the sphingosine-1-phosphate receptor S1P1/EDG-1 occurs via the hypoxia/VEGF axis. Dev Biol 2004; 268: 441-7.
134. Ishii I, Friedman B, Ye X, Kawamura S, McGiffert C, Cpntos JJ, et al. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3. J Biol Chem 2001; 276: 33697-704.
135. 3 function coordinately during embryonic angiogenesis. J Biol Chem 2004; 279: 29367-73.
136. Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003; 300: 1155-9.
137. Sadahira Y, Ruan F, Hakomori S, Igarashi Y. Sphingosine 1-phosphate, a specific endogenous signaling molecule controlling cell motility and tumor cell invasiveness. Proc Natl Acad Sci USA 1992; 89: 9686-90.
138. Bornfeldt KE, Graves LM, Raines EW, Igarashi Y, Waxman G, Yamamura S, et al. Sphingosine-1-phosphate inhibits PDGF-induced chemotaxis of human arterial smooth muscle cells: spatial and temporal modulation of PDGF chemotactic signal transduction. J Cell Biol 1995; 130: 193-206.
139. Ryu Y, Takuwa N, Sugimoto N, Sakurada S, Usui S, Okamoto H, et al. Sphingosine-1-phosphate, a platelet-derived lysophospholipid mediator, negatively regulates cellular Rac activity and cell migration in vascular smooth muscle cells. Circ Res 2002; 90: 325-32.
140. Kawa S, Kimura S, Hakomori S, Igarashi Y. Inhibition of chemotactic motility and trans-endothelial migration of human neutrophils by sphingosine 1-phosphate. FEBS Lett1997; 420: 196-200.
141. Wang F, Van Brocklyn JR, Hobson JP, Moyafagh S, Zukowska-Groiec Z, Milstien S, et al. Sphingosine 1-phosphate stimulates cell migration through a G(i)-coupled cell surface receptor. Potential involvement in angiogenesis. J Biol Chem 1999; 274: 35343-50.
142. Van Brocklyn JR, Young N, Roof R. Sphingosine-1-phosphate stimulates motility and invasiveness of human glioblastoma multiforme cells. Cancer Lett 2003; 199: 53-60.
143. Arikawa K, Takuwa N, Yamaguchi H, Sugimoto N, Kitayama J, Nagawa H, et al. Ligand-dependent inhibition of B16 melanoma cell migration and invasion via endogenous S1P2 G protein-coupled receptor. Requirement of inhibition of cellular RAC activity. J Biol Chem 2003; 278: 32841-51.
144. Osada M, Yatomi Y, Ohmori T, Ikeda H, Ozaki Y. Enhancement of sphingosine 1-phosphate-induced migration of vascular endothelial cells and smooth muscle cells by an EDG-5 antagonist. Biochem Biophys Res Commun. 2002; 299: 483-7.
145. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002; 277: 21453-7.
146. Mandala S, Haidu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002; 296: 346-9.
147. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004; 427: 355-60.
148. 3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 2004; 279: 13839-48.
149. Azuma H, Takahara S, Ichimaru N, Wang JD, Itoh Y, Otsuki Y, et al. Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models. Cancer Res 2002; 62: 1410-9.
150. Wang JD, Takahara S, Nonomura N, Ichimaru N, Toki K, Azuma H, et al. Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation. Prostate 1999; 40: 50-5.
151. Enosawa S, Suzuki S, Kakefuda T, Li XK, Amemiya H. Induction of selective cell death targeting on mature T-lymphocytes in rats by a novel immunosuppressant, FTY720.Immunopharmacology 1996; 34:171-9.
152. Nagahara Y, Enosawa S, Ikekita M, Suzuki S, Shinomiya T. Evidence that FTY720 induces T cell apoptosis in vivo. Immunopharmacol 2000; 48: 75-85.
153. Nagahara Y, Ikekita M, Shinomiya T. Immunosuppressant FTY720 induces apoptosis by direct induction of permeability transition and release of cytochrome c from mitochondria. J Immunol 2000; 165: 3250-9.
154. Matsuoka Y, Nagahara Y, Ikekita M, Shinomiya T. A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells. Br J Pharmacol 2003; 138: 1303-12.
155. Sanchez T, Estrada-Hernandez T, Paik JH, Wu MT, Venkataraman K, Brinkmann V, et al. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factorinduced vascular permeability. J Biol Chem 2003; 278: 47281-90.