Roles of Bioactive Sphingolipids in Cancer Biology and Therapeutics

  • Sahar A. Saddoughi
  • Pengfei Song
  • Besim Ogretmen
Part of the Subcellular Biochemistry book series (SCBI, volume 49)


In this chapter, roles of bioactive sphingolipids in the regulation of cancer pathogenesis and therapy will be reviewed. Sphingolipids have emerged as bioeffector molecules, which control various aspects of cell growth, proliferation, and anti-cancer therapeutics. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. On the other hand, sphingosine 1-phosphate (S1P) plays opposing roles, and induces transformation, cancer cell growth, or angiogenesis. A network of metabolic enzymes regulates the generation of ceramide and S1P, and these enzymes serve as transducers of sphingolipid-mediated responses that are coupled to various exogenous or endogenous cellular signals. Consistent with their key roles in the regulation of cancer growth and therapy, attenuation of ceramide generation and/or increased S1P levels are implicated in the development of resistance to drug-induced apoptosis, and escape from cell death. These data strongly suggest that advances in the molecular and biochemical understanding of sphingolipid metabolism and function will lead to the development of novel therapeutic strategies against human cancers, which may also help overcome drug resistance.


Apoptosis, Ceramide, Drug Resistance, Cancer Therapeutics, Sphingolipids 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abe, A., Radin, N.S., Shayman, J.A., Wotring, L.L., Zipkin, R.E., Sivakumar, R., Ruggieri, J.M., Carson, K.G., and Ganem, B. Structural and stereochemical studies of potent inhibitors of glucosylceramide synthase and tumor cell growth. J Lipid Res, 36, 1995, 611–621.PubMedGoogle Scholar
  2. Akao, Y., Banno, Y., Nakagawa, Y., Hasegawa, N., Kim, T.J., Murate, T., Igarashi, Y., and Nozawa, Y. High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation. Biochem Biophys Res Commun, 342, 2006, 1284–1290.PubMedCrossRefGoogle Scholar
  3. Alexander, S., Min, J., and Alexander, H. Dictyostelium discoideum to human cells: pharmacogenetic studies demonstrate a role for sphingolipids in chemoresistance. Biochim Biophys Acta, 1760, 2006, 301–309.PubMedGoogle Scholar
  4. Andrieu-Abadie, N. and Levade, T. Sphingomyelin hydrolysis during apoptosis. Biochim Biophys Acta, 1585, 2002, 126–134.PubMedGoogle Scholar
  5. Argraves, K.M., Wilkerson, B.A., Argraves, W.S., Fleming, P.A., Obeid, L.M., and Drake, C.J. Sphingosine-1-phosphate signaling promotes critical migratory events in vasculogenesis. J Biol Chem, 279, 2004, 50580–50590.PubMedCrossRefGoogle Scholar
  6. Baran, Y., Salas, A., Senkal, C.E., Gunduz, U., Bielawski, J., Obeid, L.M., and Ogretmen, B. Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells. J Biol Chem, 282, 2007, 10922–10934.PubMedCrossRefGoogle Scholar
  7. Bektas, M., Jolly, P.S., Muller, C., Eberle, J., Spiegel, S., and Geilen, C.C. Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression. Oncogene, 24, 2005, 178–187.PubMedCrossRefGoogle Scholar
  8. Bieberich, E., Kawaguchi, T., and Yu, R.K. N-acylated serinol is a novel ceramide mimic inducing apoptosis in neuroblastoma cells. J Biol Chem, 275, 2000, 177–181.PubMedCrossRefGoogle Scholar
  9. Bielawska, A., Greenberg, M.S., Perry, D., Jayadev, S., Shayman, J.A., McKay, C., and Hannun, Y.A. (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol as an inhibitor of ceramidase. J Biol Chem, 271, 1996, 12646–12654.PubMedCrossRefGoogle Scholar
  10. Bielawska, A., Bielawski, J., Szulc, Z.M., Mayroo, N., Liu, X., Bai, A., Elojeimy, S., Rembiesa, B., Pierce, J., Norris, J.S., and Hannun, Y.A. Novel analogs of d-e-MAPP and B13. Part 2: Signature effects on bioactive sphingolipids. Bioorg Med Chem, 16, 2008, 1032–1045.PubMedCrossRefGoogle Scholar
  11. Billich, A., Bornancin, F., Devay, P., Mechtcheriakova, D., Urtz, N., and Baumruker, T. Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem, 278, 2003, 47408–47415.PubMedCrossRefGoogle Scholar
  12. Birbes, H., El Bawab, S., Hannun, Y.A., and Obeid, L.M. Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. Faseb J, 15, 2001, 2669–2679.PubMedCrossRefGoogle Scholar
  13. Blackburn, E.H. Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett, 579, 2005, 859–862.PubMedCrossRefGoogle Scholar
  14. Borek, C. and Merrill, A.H., Jr. Sphingolipids inhibit multistage carcinogenesis and protein kinase C. Basic Life Sci, 61, 1993, 367–371.PubMedGoogle Scholar
  15. Bose, R., Verheij, M., Haimovitz-Friedman, A., Scotto, K., Fuks, Z., and Kolesnick, R. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell, 82, 1995, 405–414.PubMedCrossRefGoogle Scholar
  16. Bourbon, N.A., Sandirasegarane, L., and Kester, M. Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J Biol Chem, 277, 2002, 3286–3292.PubMedCrossRefGoogle Scholar
  17. Brinkmann, V., Cyster, J.G., and Hla, T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant, 4, 2004, 1019–1025.PubMedCrossRefGoogle Scholar
  18. Carracedo, A., Lorente, M., Egia, A., Blazquez, C., Garcia, S., Giroux, V., Malicet, C., Villuendas, R., Gironella, M., Gonzalez-Feria, L., Piris, M.A., Iovanna, J.L., Guzman, M., and Velasco, G. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell, 9, 2006, 301–312.PubMedCrossRefGoogle Scholar
  19. Cerantola, V., Vionnet, C., Aebischer, O.F., Jenny, T., Knudsen, J., and Conzelmann, A. Yeast sphingolipids do not need to contain very long chain fatty acids. Biochem J, 401, 2007, 205–216.PubMedCrossRefGoogle Scholar
  20. Chae, S.S., Paik, J.H., Furneaux, H., and Hla, T. Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. J Clin Invest, 114, 2004, 1082–1089.PubMedGoogle Scholar
  21. Chalfant, C.E., Ogretmen, B., Galadari, S., Kroesen, B.J., Pettus, B.J., and Hannun, Y.A. FAS activation induces dephosphorylation of SR proteins; dependence on the de novo generation of ceramide and activation of protein phosphatase 1. J Biol Chem, 276, 2001, 44848–44855.PubMedCrossRefGoogle Scholar
  22. Chalfant, C.E., Rathman, K., Pinkerman, R.L., Wood, R.E., Obeid, L.M., Ogretmen, B., and Hannun, Y.A. De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J Biol Chem, 277, 2002, 12587–12595.PubMedCrossRefGoogle Scholar
  23. Charles, R., Sandirasegarane, L., Yun, J., Bourbon, N., Wilson, R., Rothstein, R.P., Levison, S.W., and Kester, M. Ceramide-coated balloon catheters limit neointimal hyperplasia after stretch injury in carotid arteries. Circ Res, 87, 2000, 282–288.PubMedGoogle Scholar
  24. Chun, J. and Rosen, H. Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases. Curr Pharm Des, 12, 2006, 161–171.PubMedCrossRefGoogle Scholar
  25. Clarke, C.J. and Hannun, Y.A. Neutral sphingomyelinases and nSMase2: bridging the gaps. Biochim Biophys Acta, 1758, 2006, 1893–1901.PubMedCrossRefGoogle Scholar
  26. Clarke, C.J., Snook, C.F., Tani, M., Matmati, N., Marchesini, N., and Hannun, Y.A. The extended family of neutral sphingomyelinases. Biochemistry, 45, 2006, 11247–11256.PubMedCrossRefGoogle Scholar
  27. Crawford, K.W., Bittman, R., Chun, J., Byun, H.S., and Bowen, W.D. Novel ceramide analogues display selective cytotoxicity in drug-resistant breast tumor cell lines compared to normal breast epithelial cells. Cell Mol Biol (Noisy-le-grand), 49, 2003, 1017–1023.Google Scholar
  28. Cremesti, A., Paris, F., Grassme, H., Holler, N., Tschopp, J., Fuks, Z., Gulbins, E., and Kolesnick, R. Ceramide enables fas to cap and kill. J Biol Chem, 276, 2001, 23954–23961.PubMedCrossRefGoogle Scholar
  29. D'Angelo, G., Polishchuk, E., Di Tullio, G., Santoro, M., Di Campli, A., Godi, A., West, G., Bielawski, J., Chuang, C.C., van der Spoel, A.C., Platt, F.M., Hannun, Y.A., Polishchuk, R., Mattjus, P., and De Matteis, M.A. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature, 449, 2007, 62–67.PubMedCrossRefGoogle Scholar
  30. Dahm, F., Bielawska, A., Nocito, A., Georgiev, P., Szulc, Z.M., Bielawski, J., Jochum, W., Dindo, D., Hannun, Y.A., and Clavien, P.A. Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice. Br J Cancer, 98, 2008, 98–105.PubMedCrossRefGoogle Scholar
  31. Davis, M.D., Clemens, J.J., Macdonald, T.L., and Lynch, K.R. Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem, 280, 2005, 9833–9841.PubMedCrossRefGoogle Scholar
  32. Dbaibo, G.S., Pushkareva, M.Y., Jayadev, S., Schwarz, J.K., Horowitz, J.M., Obeid, L.M., and Hannun, Y.A. Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest. Proc Natl Acad Sci U S A, 92, 1995, 1347–1351.PubMedCrossRefGoogle Scholar
  33. Dbaibo, G.S., Perry, D.K., Gamard, C.J., Platt, R., Poirier, G.G., Obeid, L.M., and Hannun, Y.A. Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway. J Exp Med, 185, 1997, 481–490.PubMedCrossRefGoogle Scholar
  34. De Rosa, M.F., Sillence, D., Ackerley, C., and Lingwood, C. Role of multiple drug resistance protein 1 in neutral but not acidic glycosphingolipid biosynthesis. J Biol Chem, 279, 2004, 7867–7876.PubMedCrossRefGoogle Scholar
  35. Dindo, D., Dahm, F., Szulc, Z., Bielawska, A., Obeid, L.M., Hannun, Y.A., Graf, R., and Clavien, P.A. Cationic long-chain ceramide LCL-30 induces cell death by mitochondrial targeting in SW403 cells. Mol Cancer Ther, 5, 2006, 1520–1529.PubMedCrossRefGoogle Scholar
  36. Dobrowsky, R.T. and Hannun, Y.A. Ceramide stimulates a cytosolic protein phosphatase. J Biol Chem, 267, 1992, 5048–5051.PubMedGoogle Scholar
  37. Dobrowsky, R.T., Kamibayashi, C., Mumby, M.C., and Hannun, Y.A. Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem, 268, 1993, 15523–15530.PubMedGoogle Scholar
  38. Dobrowsky, R.T., Werner, M.H., Castellino, A.M., Chao, M.V., and Hannun, Y.A. Activation of the sphingomyelin cycle through the low-affinity neurotrophin receptor. Science, 265, 1994, 1596–1599.PubMedCrossRefGoogle Scholar
  39. Dolgachev, V., Farooqui, M.S., Kulaeva, O.I., Tainsky, M.A., Nagy, B., Hanada, K., and Separovic, D. De novo ceramide accumulation due to inhibition of its conversion to complex sphingolipids in apoptotic photosensitized cells. J Biol Chem, 279, 2004, 23238–23249.PubMedCrossRefGoogle Scholar
  40. Fishbein, J.D., Dobrowsky, R.T., Bielawska, A., Garrett, S., and Hannun, Y.A. Ceramide-mediated growth inhibition and CAPP are conserved in Saccharomyces cerevisiae. J Biol Chem, 268, 1993, 9255–9261.PubMedGoogle Scholar
  41. Fox, T.E., Finnegan, C.M., Blumenthal, R., and Kester, M. The clinical potential of sphingolipid-based therapeutics. Cell Mol Life Sci, 63, 2006, 1017–1023.PubMedCrossRefGoogle Scholar
  42. Fox, T.E., Houck, K.L., O'Neill, S.M., Nagarajan, M., Stover, T.C., Pomianowski, P.T., Unal, O., Yun, J.K., Naides, S.J., and Kester, M. Ceramide recruits and activates protein kinase C zeta (PKC zeta) within structured membrane microdomains. J Biol Chem, 282, 2007, 12450–12457.PubMedCrossRefGoogle Scholar
  43. French, K.J., Upson, J.J., Keller, S.N., Zhuang, Y., Yun, J.K., and Smith, C.D. Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther, 318, 2006, 596–603.PubMedCrossRefGoogle Scholar
  44. Futerman, A.H. and Hannun, Y.A. The complex life of simple sphingolipids. EMBO Rep, 5, 2004, 777–782.PubMedCrossRefGoogle Scholar
  45. Futerman, A.H. and Riezman, H. The ins and outs of sphingolipid synthesis. Trends Cell Biol, 15, 2005, 312–318.PubMedCrossRefGoogle Scholar
  46. Gouaze-Andersson, V. and Cabot, M.C. Glycosphingolipids and drug resistance. Biochim Biophys Acta, 1758, 2006, 2096–2103.PubMedCrossRefGoogle Scholar
  47. Gouaze-Andersson, V., Yu, J.Y., Kreitenberg, A.J., Bielawska, A., Giuliano, A.E., and Cabot, M.C. Ceramide and glucosylceramide upregulate expression of the multidrug resistance gene MDR1 in cancer cells. Biochim Biophys Acta, 1771, 2007, 1407–1417.PubMedGoogle Scholar
  48. Gouaze, V., Liu, Y.Y., Prickett, C.S., Yu, J.Y., Giuliano, A.E., and Cabot, M.C. Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs. Cancer Res, 65, 2005, 3861–3867.PubMedCrossRefGoogle Scholar
  49. Gouaze, V., Yu, J.Y., Bleicher, R.J., Han, T.Y., Liu, Y.Y., Wang, H., Gottesman, M.M., Bitterman, A., Giuliano, A.E., and Cabot, M.C. Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy. Mol Cancer Ther, 3, 2004, 633–639.PubMedGoogle Scholar
  50. Goulding, C.W., Giuliano, A.E., and Cabot, M.C. SDZ PSC 833 the drug resistance modulator activates cellular ceramide formation by a pathway independent of P-glycoprotein. Cancer Lett, 149, 2000, 143–151.PubMedCrossRefGoogle Scholar
  51. Guillas, I., Kirchman, P.A., Chuard, R., Pfefferli, M., Jiang, J.C., Jazwinski, S.M., and Conzelmann, A. C26-CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p. Embo J, 20, 2001, 2655–2665.PubMedCrossRefGoogle Scholar
  52. Hanada, K., Kumagai, K., Yasuda, S., Miura, Y., Kawano, M., Fukasawa, M., and Nishijima, M. Molecular machinery for non-vesicular trafficking of ceramide. Nature, 426, 2003, 803–809.PubMedCrossRefGoogle Scholar
  53. Hannun, Y.A. and Obeid, L.M. The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem, 277, 2002, 25847–25850.PubMedCrossRefGoogle Scholar
  54. Heinrich, M., Neumeyer, J., Jakob, M., Hallas, C., Tchikov, V., Winoto-Morbach, S., Wickel, M., Schneider-Brachert, W., Trauzold, A., Hethke, A., and Schutze, S. Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ, 11, 2004, 550–563.PubMedCrossRefGoogle Scholar
  55. Herrera, B., Carracedo, A., Diez-Zaera, M., Gomez del Pulgar, T., Guzman, M., and Velasco, G. The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp Cell Res, 312, 2006, 2121–2131.PubMedCrossRefGoogle Scholar
  56. Hinrichs, J.W., Klappe, K., and Kok, J.W. Rafts as missing link between multidrug resistance and sphingolipid metabolism. J Membr Biol, 203, 2005, 57–64.PubMedCrossRefGoogle Scholar
  57. Hla, T. Physiological and pathological actions of sphingosine 1-phosphate. Semin Cell Dev Biol, 15, 2004, 513–520.PubMedCrossRefGoogle Scholar
  58. Holman, D.H., Turner, L.S., El-Zawahry, A., Elojeimy, S., Liu, X., Bielawski, J., Szulc, Z.M., Norris, K., Zeidan, Y.H., Hannun, Y.A., Bielawska, A., and Norris, J.S. Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells. Cancer Chemother Pharmacol, 61, 2008, 231–242.PubMedCrossRefGoogle Scholar
  59. Jazwinski, S.M. and Conzelmann, A. LAG1 puts the focus on ceramide signaling. Int J Biochem Cell Biol, 34, 2002, 1491–1495.PubMedCrossRefGoogle Scholar
  60. Jiang, Q., Wong, J., Fyrst, H., Saba, J.D., and Ames, B.N. gamma-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. Proc Natl Acad Sci U S A, 101, 2004, 17825–17830.PubMedCrossRefGoogle Scholar
  61. Kageyama-Yahara, N. and Riezman, H. Transmembrane topology of ceramide synthase in yeast. Biochem J, 398, 2006, 585–593.PubMedCrossRefGoogle Scholar
  62. Karahatay, S., Thomas, K., Koybasi, S., Senkal, C.E., Elojeimy, S., Liu, X., Bielawski, J., Day, T.A., Gillespie, M.B., Sinha, D., Norris, J.S., Hannun, Y.A., and Ogretmen, B. Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis. Cancer Lett, 256, 2007, 101–111.PubMedCrossRefGoogle Scholar
  63. Kawamori, T., Osta, W., Johnson, K.R., Pettus, B.J., Bielawski, J., Tanaka, T., Wargovich, M.J., Reddy, B.S., Hannun, Y.A., Obeid, L.M., and Zhou, D. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. Faseb J, 20, 2006, 386–388.PubMedGoogle Scholar
  64. Kok, J.W. and Sietsma, H. Sphingolipid metabolism enzymes as targets for anticancer therapy. Curr Drug Targets, 5, 2004, 375–382.PubMedCrossRefGoogle Scholar
  65. Koybasi, S., Senkal, C.E., Sundararaj, K., Spassieva, S., Bielawski, J., Osta, W., Day, T.A., Jiang, J.C., Jazwinski, S.M., Hannun, Y.A., Obeid, L.M., and Ogretmen, B. Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas. J Biol Chem, 279, 2004, 44311–44319.PubMedCrossRefGoogle Scholar
  66. Kraveka, J.M., Li, L., Szulc, Z.M., Bielawski, J., Ogretmen, B., Hannun, Y.A., Obeid, L.M., and Bielawska, A. Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J Biol Chem, 282, 2007, 16718–16728.PubMedCrossRefGoogle Scholar
  67. Kudo, N., Kumagai, K., Tomishige, N., Yamaji, T., Wakatsuki, S., Nishijima, M., Hanada, K., and Kato, R. Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide. Proc Natl Acad Sci U S A, 105, 2008, 488–493.PubMedCrossRefGoogle Scholar
  68. Kumagai, K., Yasuda, S., Okemoto, K., Nishijima, M., Kobayashi, S., and Hanada, K. CERT mediates intermembrane transfer of various molecular species of ceramides. J Biol Chem, 280, 2005, 6488–6495.PubMedCrossRefGoogle Scholar
  69. Lahiri, S. and Futerman, A.H. LASS5 is a bona fide dihydroceramide synthase that selectively utilizes palmitoyl-CoA as acyl donor. J Biol Chem, 280, 2005, 33735–33738.PubMedCrossRefGoogle Scholar
  70. LaMontagne, K., Littlewood-Evans, A., Schnell, C., O'Reilly, T., Wyder, L., Sanchez, T., Probst, B., Butler, J., Wood, A., Liau, G., Billy, E., Theuer, A., Hla, T., and Wood, J. Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization. Cancer Res, 66, 2006, 221–231.PubMedCrossRefGoogle Scholar
  71. Laviad, E.L., Albee, L., Pankova-Kholmyansky, I., Epstein, S., Park, H., Merrill, A.H., Jr., and Futerman, A.H. Characterization of ceramide synthase 2: Tissue distribution, substrate specificity and inhibition by sphingosine 1-phosphate. J Biol Chem 2007, in press.Google Scholar
  72. Lee, J.Y., Bielawska, A.E., and Obeid, L.M. Regulation of cyclin-dependent kinase 2 activity by ceramide. Exp Cell Res, 261, 2000, 303–311.PubMedCrossRefGoogle Scholar
  73. Lee, S.J. Expression of growth/differentiation factor 1 in the nervous system: conservation of a bicistronic structure. Proc Natl Acad Sci U S A, 88, 1991, 4250–4254.PubMedCrossRefGoogle Scholar
  74. Liu, H., Toman, R.E., Goparaju, S.K., Maceyka, M., Nava, V.E., Sankala, H., Payne, S.G., Bektas, M., Ishii, I., Chun, J., Milstien, S., and Spiegel, S. Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J Biol Chem, 278, 2003, 40330–40336.PubMedCrossRefGoogle Scholar
  75. Liu, X., Elojeimy, S., Turner, L.S., Mahdy, A.E., Zeidan, Y.H., Bielawska, A., Bielawski, J., Dong, J.Y., El-Zawahry, A.M., Guo, G.W., Hannun, Y.A., Holman, D.H., Rubinchik, S., Szulc, Z., Keane, T.E., Tavassoli, M., and Norris, J.S. Acid ceramidase inhibition: a novel target for cancer therapy. Front Biosci, 13, 2008, 2293–2298.PubMedCrossRefGoogle Scholar
  76. Maceyka, M., Payne, S.G., Milstien, S., and Spiegel, S. Sphingosine kinase, sphingosine-1-phosphate, and apoptosis. Biochim Biophys Acta, 1585, 2002, 193–201.PubMedGoogle Scholar
  77. Maurer, B.J., Metelitsa, L.S., Seeger, R.C., Cabot, M.C., and Reynolds, C.P. Increase of ceramide and induction of mixed apoptosis/necrosis by N-(4-hydroxyphenyl)- retinamide in neuroblastoma cell lines. J Natl Cancer Inst, 91, 1999, 1138–1146.PubMedCrossRefGoogle Scholar
  78. Maurer, B.J., Melton, L., Billups, C., Cabot, M.C., and Reynolds, C.P. Synergistic cytotoxicity in solid tumor cell lines between N-(4-hydroxyphenyl)retinamide and modulators of ceramide metabolism. J Natl Cancer Inst, 92, 2000, 1897–1909.PubMedCrossRefGoogle Scholar
  79. Meng, A., Luberto, C., Meier, P., Bai, A., Yang, X., Hannun, Y.A., and Zhou, D. Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells. Exp Cell Res, 292, 2004, 385–392.PubMedCrossRefGoogle Scholar
  80. Merrill, A.H., Jr., Wang, E., and Mullins, R.E. Kinetics of long-chain (sphingoid) base biosynthesis in intact LM cells: effects of varying the extracellular concentrations of serine and fatty acid precursors of this pathway. Biochemistry, 27, 1988, 340–345.PubMedCrossRefGoogle Scholar
  81. Mesika, A., Ben-Dor, S., Laviad, E.L., and Futerman, A.H. A new functional motif in Hox domain-containing ceramide synthases: identification of a novel region flanking the Hox and TLC domains essential for activity. J Biol Chem, 282, 2007, 27366–27373.PubMedCrossRefGoogle Scholar
  82. Michel, C., van Echten-Deckert, G., Rother, J., Sandhoff, K., Wang, E., and Merrill, A.H., Jr. Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J Biol Chem, 272, 1997, 22432–22437.PubMedCrossRefGoogle Scholar
  83. Min, J., Van Veldhoven, P.P., Zhang, L., Hanigan, M.H., Alexander, H., and Alexander, S. Sphingosine-1-phosphate lyase regulates sensitivity of human cells to select chemotherapy drugs in a p38-dependent manner. Mol Cancer Res, 3, 2005, 287–296.PubMedCrossRefGoogle Scholar
  84. Min, J., Mesika, A., Sivaguru, M., Van Veldhoven, P.P., Alexander, H., Futerman, A.H., and Alexander, S. (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1. Mol Cancer Res, 5, 2007, 801–812.PubMedCrossRefGoogle Scholar
  85. Minutolo, F., Sala, G., Bagnacani, A., Bertini, S., Carboni, I., Placanica, G., Prota, G., Rapposelli, S., Sacchi, N., Macchia, M., and Ghidoni, R. Synthesis of a resveratrol analogue with high ceramide-mediated proapoptotic activity on human breast cancer cells. J Med Chem, 48, 2005, 6783–6786.PubMedCrossRefGoogle Scholar
  86. Mitra, P., Maceyka, M., Payne, S.G., Lamour, N., Milstien, S., Chalfant, C.E., and Spiegel, S. Ceramide kinase regulates growth and survival of A549 human lung adenocarcinoma cells. FEBS Lett, 581, 2007, 735–740.PubMedCrossRefGoogle Scholar
  87. Mizugishi, K., Yamashita, T., Olivera, A., Miller, G.F., Spiegel, S., and Proia, R.L. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol, 25, 2005, 11113–11121.PubMedCrossRefGoogle Scholar
  88. Mizutani, Y., Kihara, A., and Igarashi, Y. Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J, 390, 2005, 263–271.PubMedCrossRefGoogle Scholar
  89. Modica-Napolitano, J.S. and Aprille, J.R. Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells. Adv Drug Deliv Rev, 49, 2001, 63–70.PubMedCrossRefGoogle Scholar
  90. Modrak, D.E., Gold, D.V., and Goldenberg, D.M. Sphingolipid targets in cancer therapy. Mol Cancer Ther, 5, 2006, 200–208.PubMedCrossRefGoogle Scholar
  91. Modrak, D.E., Cardillo, T.M., Newsome, G.A., Goldenberg, D.M., and Gold, D.V. Synergistic interaction between sphingomyelin and gemcitabine potentiates ceramide-mediated apoptosis in pancreatic cancer. Cancer Res, 64, 2004, 8405–8410.PubMedCrossRefGoogle Scholar
  92. Morales, A., Paris, R., Villanueva, A., Llacuna, L., Garcia-Ruiz, C., and Fernandez-Checa, J.C. Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo. Oncogene, 26, 2007, 905–916.PubMedCrossRefGoogle Scholar
  93. Nagiec, M.M., Lester, R.L., and Dickson, R.C. Sphingolipid synthesis: identification and characterization of mammalian cDNAs encoding the Lcb2 subunit of serine palmitoyltransferase. Gene, 177, 1996, 237–241.PubMedCrossRefGoogle Scholar
  94. Nava, V.E., Hobson, J.P., Murthy, S., Milstien, S., and Spiegel, S. Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. Exp Cell Res, 281, 2002, 115–127.PubMedCrossRefGoogle Scholar
  95. Norris-Cervetto, E., Callaghan, R., Platt, F.M., Dwek, R.A., and Butters, T.D. Inhibition of glucosylceramide synthase does not reverse drug resistance in cancer cells. J Biol Chem, 279, 2004, 40412–40418.PubMedCrossRefGoogle Scholar
  96. Novgorodov, S.A., Szulc, Z.M., Luberto, C., Jones, J.A., Bielawski, J., Bielawska, A., Hannun, Y.A., and Obeid, L.M. Positively charged ceramide is a potent inducer of mitochondrial permeabilization. J Biol Chem, 280, 2005, 16096–16105.PubMedCrossRefGoogle Scholar
  97. Obeid, L.M. and Hannun, Y.A. Ceramide, stress, and a "LAG" in aging. Sci Aging Knowledge Environ, 2003, 2003, pe27.CrossRefGoogle Scholar
  98. Ogretmen, B. Sphingolipids in cancer: regulation of pathogenesis and therapy. FEBS Lett, 580, 2006, 5467–5476.PubMedCrossRefGoogle Scholar
  99. Ogretmen, B. and Hannun, Y.A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer, 4, 2004, 604–616.PubMedCrossRefGoogle Scholar
  100. Ogretmen, B. and Hannun, Y.A. Updates on functions of ceramide in chemotherapy-induced cell death and in multidrug resistance. Drug Resist Updat, 4, 2001, 368–377.PubMedCrossRefGoogle Scholar
  101. Ogretmen, B., Kraveka, J.M., Schady, D., Usta, J., Hannun, Y.A., and Obeid, L.M. Molecular mechanisms of ceramide-mediated telomerase inhibition in the A549 human lung adenocarcinoma cell line. J Biol Chem, 276, 2001a, 32506–32514.CrossRefGoogle Scholar
  102. Ogretmen, B., Schady, D., Usta, J., Wood, R., Kraveka, J.M., Luberto, C., Birbes, H., Hannun, Y.A., and Obeid, L.M. Role of ceramide in mediating the inhibition of telomerase activity in A549 human lung adenocarcinoma cells. J Biol Chem, 276, 2001b, 24901–24910.CrossRefGoogle Scholar
  103. Ogretmen, B., Pettus, B.J., Rossi, M.J., Wood, R., Usta, J., Szulc, Z., Bielawska, A., Obeid, L.M., and Hannun, Y.A. Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide. J Biol Chem, 277, 2002, 12960–12969.PubMedCrossRefGoogle Scholar
  104. Okazaki, T., Bell, R.M., and Hannun, Y.A. Sphingomyelin turnover induced by vitamin D3 in HL-60 cells. Role in cell differentiation. J Biol Chem, 264, 1989, 19076–19080.PubMedGoogle Scholar
  105. Oskouian, B., Sooriyakumaran, P., Borowsky, A.D., Crans, A., Dillard-Telm, L., Tam, Y.Y., Bandhuvula, P., and Saba, J.D. Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Proc Natl Acad Sci U S A, 103, 2006, 17384–17389.PubMedCrossRefGoogle Scholar
  106. Park, J.H. and Schuchman, E.H. Acid ceramidase and human disease. Biochim Biophys Acta, 1758, 2006, 2133–2138.PubMedCrossRefGoogle Scholar
  107. Paugh, S.W., Payne, S.G., Barbour, S.E., Milstien, S., and Spiegel, S. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett, 554, 2003, 189–193.PubMedCrossRefGoogle Scholar
  108. Pchejetski, D., Golzio, M., Bonhoure, E., Calvet, C., Doumerc, N., Garcia, V., Mazerolles, C., Rischmann, P., Teissie, J., Malavaud, B., and Cuvillier, O. Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res, 65, 2005, 11667–11675.PubMedCrossRefGoogle Scholar
  109. Pettus, B.J., Chalfant, C.E., and Hannun, Y.A. Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta, 1585, 2002, 114–125.PubMedGoogle Scholar
  110. Pettus, B.J., Bielawski, J., Porcelli, A.M., Reames, D.L., Johnson, K.R., Morrow, J., Chalfant, C.E., Obeid, L.M., and Hannun, Y.A. The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha. Faseb J, 17, 2003, 1411–1421.PubMedCrossRefGoogle Scholar
  111. Pewzner-Jung, Y., Ben-Dor, S., and Futerman, A.H. When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: Insights into the regulation of ceramide synthesis. J Biol Chem, 281, 2006, 25001–25005.PubMedCrossRefGoogle Scholar
  112. Plo, I., Ghandour, S., Feutz, A.C., Clanet, M., Laurent, G., and Bettaieb, A. Involvement of de novo ceramide biosynthesis in lymphotoxin-induced oligodendrocyte death. Neuroreport, 10, 1999, 2373–2376.PubMedCrossRefGoogle Scholar
  113. Radin, N.S. The development of aggressive cancer: a possible role for sphingolipids. Cancer Invest, 20, 2002, 779–786.PubMedCrossRefGoogle Scholar
  114. Raisova, M., Bektas, M., Wieder, T., Daniel, P., Eberle, J., Orfanos, C.E., and Geilen, C.C. Resistance to CD95/Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release. FEBS Lett, 473, 2000, 27–32.PubMedCrossRefGoogle Scholar
  115. Rao, R.P., Yuan, C., Allegood, J.C., Rawat, S.S., Edwards, M.B., Wang, X., Merrill, A.H., Jr., Acharya, U., and Acharya, J.K. Ceramide transfer protein function is essential for normal oxidative stress response and lifespan. Proc Natl Acad Sci U S A, 104, 2007, 11364–11369.PubMedCrossRefGoogle Scholar
  116. Reynolds, C.P., Maurer, B.J., and Kolesnick, R.N. Ceramide synthesis and metabolism as a target for cancer therapy. Cancer Lett, 206, 2004, 169–180.PubMedCrossRefGoogle Scholar
  117. Riebeling, C., Allegood, J.C., Wang, E., Merrill, A.H., Jr., and Futerman, A.H. Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors. J Biol Chem, 278, 2003, 43452–43459.PubMedCrossRefGoogle Scholar
  118. Rosen, H. and Goetzl, E.J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol, 5, 2005, 560–570.PubMedCrossRefGoogle Scholar
  119. Rossi, M.J., Sundararaj, K., Koybasi, S., Phillips, M.S., Szulc, Z.M., Bielawska, A., Day, T.A., Obeid, L.M., Hannun, Y.A., and Ogretmen, B. Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells. Otolaryngol Head Neck Surg, 132, 2005, 55–62.PubMedCrossRefGoogle Scholar
  120. Saad, A.F., Meacham, W.D., Bai, A., Anelli, V., Elojeimy, S., Mahdy, A.E., Turner, L.S., Cheng, J., Bielawska, A., Bielawski, J., Keane, T.E., Obeid, L.M., Hannun, Y.A., Norris, J.S., and Liu, X. The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy. Cancer Biol Ther, 6, 2007, 1455–1460.PubMedCrossRefGoogle Scholar
  121. Samsel, L., Zaidel, G., Drumgoole, H.M., Jelovac, D., Drachenberg, C., Rhee, J.G., Brodie, A.M., Bielawska, A., and Smyth, M.J. The ceramide analog, B13, induces apoptosis in prostate cancer cell lines and inhibits tumor growth in prostate cancer xenografts. Prostate, 58, 2004, 382–393.PubMedCrossRefGoogle Scholar
  122. Sankala, H.M., Hait, N.C., Paugh, S.W., Shida, D., Lepine, S., Elmore, L.W., Dent, P., Milstien, S., and Spiegel, S. Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin. Cancer Res, 67, 2007, 10466–10474.PubMedCrossRefGoogle Scholar
  123. Santana, P., Pena, L.A., Haimovitz-Friedman, A., Martin, S., Green, D., McLoughlin, M., Cordon-Cardo, C., Schuchman, E.H., Fuks, Z., and Kolesnick, R. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell, 86, 1996, 189–199.PubMedCrossRefGoogle Scholar
  124. Sarkar, S., Maceyka, M., Hait, N.C., Paugh, S.W., Sankala, H., Milstien, S., and Spiegel, S. Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells. FEBS Lett, 579, 2005, 5313–5317.PubMedCrossRefGoogle Scholar
  125. Scarlatti, F., Sala, G., Somenzi, G., Signorelli, P., Sacchi, N., and Ghidoni, R. Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. Faseb J, 17, 2003, 2339–2341.PubMedGoogle Scholar
  126. Scarlatti, F., Sala, G., Ricci, C., Maioli, C., Milani, F., Minella, M., Botturi, M., and Ghidoni, R. Resveratrol sensitization of DU145 prostate cancer cells to ionizing radiation is associated to ceramide increase. Cancer Lett, 253, 2007, 124–130.PubMedCrossRefGoogle Scholar
  127. Schmelz, E.M., Sullards, M.C., Dillehay, D.L., and Merrill, A.H., Jr. Colonic cell proliferation and aberrant crypt foci formation are inhibited by dairy glycosphingolipids in 1, 2-dimethylhydrazine-treated CF1 mice. J Nutr, 130, 2000, 522–527.PubMedGoogle Scholar
  128. Schmelz, E.M., Dillehay, D.L., Webb, S.K., Reiter, A., Adams, J., and Merrill, A.H., Jr. Sphingomyelin consumption suppresses aberrant colonic crypt foci and increases the proportion of adenomas versus adenocarcinomas in CF1 mice treated with 1,2-dimethylhydrazine: implications for dietary sphingolipids and colon carcinogenesis. Cancer Res, 56, 1996, 4936–4941.PubMedGoogle Scholar
  129. Schulz, A., Mousallem, T., Venkataramani, M., Persaud-Sawin, D.A., Zucker, A., Luberto, C., Bielawska, A., Bielawski, J., Holthuis, J.C., Jazwinski, S.M., Kozhaya, L., Dbaibo, G.S., and Boustany, R.M. The CLN9 protein, a regulator of dihydroceramide synthase. J Biol Chem, 281, 2006, 2784–2794.PubMedCrossRefGoogle Scholar
  130. Segui, B., Cuvillier, O., Adam-Klages, S., Garcia, V., Malagarie-Cazenave, S., Leveque, S., Caspar-Bauguil, S., Coudert, J., Salvayre, R., Kronke, M., and Levade, T. Involvement of FAN in TNF-induced apoptosis. J Clin Invest, 108, 2001, 143–151.PubMedGoogle Scholar
  131. Selzner, M., Bielawska, A., Morse, M.A., Rudiger, H.A., Sindram, D., Hannun, Y.A., and Clavien, P.A. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res, 61, 2001, 1233–1240.PubMedGoogle Scholar
  132. Senchenkov, A., Litvak, D.A., and Cabot, M.C. Targeting ceramide metabolism--a strategy for overcoming drug resistance. J Natl Cancer Inst, 93, 2001, 347–357.PubMedCrossRefGoogle Scholar
  133. Senkal, C.E., Ponnusamy, S., Rossi, M.J., Bialewski, J., Sinha, D., Jiang, J.C., Jazwinski, S.M., Hannun, Y.A., and Ogretmen, B. Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas. Mol Cancer Ther, 6, 2007, 712–722.PubMedCrossRefGoogle Scholar
  134. Senkal, C.E., Ponnusamy, S., Rossi, M.J., Sundararaj, K., Szulc, Z., Bielawski, J., Bielawska, A., Meyer, M., Cobanoglu, B., Koybasi, S., Sinha, D., Day, T.A., Obeid, L.M., Hannun, Y.A., and Ogretmen, B. Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo. J Pharmacol Exp Ther, 317, 2006, 1188–1199.PubMedCrossRefGoogle Scholar
  135. Smyth, M.J., Perry, D.K., Zhang, J., Poirier, G.G., Hannun, Y.A., and Obeid, L.M. prICE: a downstream target for ceramide-induced apoptosis and for the inhibitory action of Bcl-2. Biochem J, 316 (Pt 1), 1996, 25–28.PubMedGoogle Scholar
  136. Snook, C.F., Jones, J.A., and Hannun, Y.A. Sphingolipid-binding proteins. Biochim Biophys Acta, 1761, 2006, 927–946.PubMedGoogle Scholar
  137. Spassieva, S., Seo, J.G., Jiang, J.C., Bielawski, J., Alvarez-Vasquez, F., Jazwinski, S.M., Hannun, Y.A., and Obeid, L.M. Necessary role for the Lag1p motif in (dihydro)ceramide synthase activity. J Biol Chem, 281, 2006, 33931–33938.PubMedCrossRefGoogle Scholar
  138. 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.PubMedCrossRefGoogle Scholar
  139. Stover, T.C., Sharma, A., Robertson, G.P., and Kester, M. Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin Cancer Res, 11, 2005, 3465–3474.PubMedCrossRefGoogle Scholar
  140. Struckhoff, A.P., Bittman, R., Burow, M.E., Clejan, S., Elliott, S., Hammond, T., Tang, Y., and Beckman, B.S. Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J Pharmacol Exp Ther, 309, 2004, 523–532.PubMedCrossRefGoogle Scholar
  141. Sugiura, M., Kono, K., Liu, H., Shimizugawa, T., Minekura, H., Spiegel, S., and Kohama, T. Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization. J Biol Chem, 277, 2002, 23294–23300.PubMedCrossRefGoogle Scholar
  142. Sultan, I., Senkal, C.E., Ponnusamy, S., Bielawski, J., Szulc, Z., Bielawska, A., Hannun, Y.A., and Ogretmen, B. Regulation of the sphingosine-recycling pathway for ceramide generation by oxidative stress, and its role in controlling c-Myc/Max function. Biochem J, 393, 2006, 513–521.PubMedCrossRefGoogle Scholar
  143. Sundararaj, K.P., Wood, R.E., Ponnusamy, S., Salas, A.M., Szulc, Z., Bielawska, A., Obeid, L.M., Hannun, Y.A., and Ogretmen, B. Rapid shortening of telomere length in response to ceramide involves the inhibition of telomere binding activity of nuclear glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem, 279, 2004, 6152–6162.PubMedCrossRefGoogle Scholar
  144. Suomalainen, L., Pentikainen, V., and Dunkel, L. Sphingosine-1-phosphate inhibits nuclear factor kappaB activation and germ cell apoptosis in the human testis independently of its receptors. Am J Pathol, 166, 2005, 773–781.PubMedGoogle Scholar
  145. Swanton, C., Marani, M., Pardo, O., Warne, P.H., Kelly, G., Sahai, E., Elustondo, F., Chang, J., Temple, J., Ahmed, A.A., Brenton, J.D., Downward, J., and Nicke, B. Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. Cancer Cell, 11, 2007, 498–512.PubMedCrossRefGoogle Scholar
  146. Szulc, Z.M., Bielawski, J., Gracz, H., Gustilo, M., Mayroo, N., Hannun, Y.A., Obeid, L.M., and Bielawska, A. Tailoring structure-function and targeting properties of ceramides by site-specific cationization. Bioorg Med Chem, 14, 2006, 7083–7104.PubMedCrossRefGoogle Scholar
  147. Taha, T.A., Hannun, Y.A., and Obeid, L.M. Sphingosine kinase: biochemical and cellular regulation and role in disease. J Biochem Mol Biol, 39, 2006a, 113–131.Google Scholar
  148. Taha, T.A., Kitatani, K., El-Alwani, M., Bielawski, J., Hannun, Y.A., and Obeid, L.M. Loss of sphingosine kinase-1 activates the intrinsic pathway of programmed cell death: modulation of sphingolipid levels and the induction of apoptosis. Faseb J, 20, 2006b, 482–484.Google Scholar
  149. Testai, F.D., Landek, M.A., and Dawson, G. Regulation of sphingomyelinases in cells of the oligodendrocyte lineage. J Neurosci Res, 75, 2004, 66–74.PubMedCrossRefGoogle Scholar
  150. Thomas, D.A., Sarris, A.H., Cortes, J., Faderl, S., O'Brien, S., Giles, F.J., Garcia-Manero, G., Rodriguez, M.A., Cabanillas, F., and Kantarjian, H. Phase II study of sphingosomal vincristine in patients with recurrent or refractory adult acute lymphocytic leukemia. Cancer, 106, 2006, 120–127.PubMedCrossRefGoogle Scholar
  151. Thon, L., Mohlig, H., Mathieu, S., Lange, A., Bulanova, E., Winoto-Morbach, S., Schutze, S., Bulfone-Paus, S., and Adam, D. Ceramide mediates caspase-independent programmed cell death. Faseb J, 19, 2005, 1945–1956.PubMedCrossRefGoogle Scholar
  152. Tilly, J.L. and Kolesnick, R.N. Sphingolipids, apoptosis, cancer treatments and the ovary: investigating a crime against female fertility. Biochim Biophys Acta, 1585, 2002, 135–138.PubMedGoogle Scholar
  153. Van Brocklyn, J., Letterle, C., Snyder, P., and Prior, T. Sphingosine-1-phosphate stimulates human glioma cell proliferation through Gi-coupled receptors: role of ERK MAP kinase and phosphatidylinositol 3-kinase beta. Cancer Lett, 181, 2002, 195–204.PubMedCrossRefGoogle Scholar
  154. Van der Luit, A.H., Budde, M., Zerp, S., Caan, W., Klarenbeek, J.B., Verheij, M., and Van Blitterswijk, W.J. Resistance to alkyl-lysophospholipid-induced apoptosis due to downregulated sphingomyelin synthase 1 expression with consequent sphingomyelin- and cholesterol-deficiency in lipid rafts. Biochem J, 401, 2007, 541–549.PubMedCrossRefGoogle Scholar
  155. van Vlerken, L.E., Duan, Z., Seiden, M.V., and Amiji, M.M. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res, 67, 2007, 4843–4850.PubMedCrossRefGoogle Scholar
  156. Veldman, R.J., Zerp, S., van Blitterswijk, W.J., and Verheij, M. N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx. Br J Cancer, 90, 2004, 917–925.PubMedCrossRefGoogle Scholar
  157. Veldman, R.J., Mita, A., Cuvillier, O., Garcia, V., Klappe, K., Medin, J.A., Campbell, J.D., Carpentier, S., Kok, J.W., and Levade, T. The absence of functional glucosylceramide synthase does not sensitize melanoma cells for anticancer drugs. Faseb J, 17, 2003, 1144–1146.PubMedGoogle Scholar
  158. Venable, M.E., Lee, J.Y., Smyth, M.J., Bielawska, A., and Obeid, L.M. Role of ceramide in cellular senescence. J Biol Chem, 270, 1995, 30701–30708.PubMedCrossRefGoogle Scholar
  159. Venkataraman, K., Riebeling, C., Bodennec, J., Riezman, H., Allegood, J.C., Sullards, M.C., Merrill, A.H., Jr., and Futerman, A.H. Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells. J Biol Chem, 277, 2002, 35642–35649.PubMedCrossRefGoogle Scholar
  160. Visentin, B., Vekich, J.A., Sibbald, B.J., Cavalli, A.L., Moreno, K.M., Matteo, R.G., Garland, W.A., Lu, Y., Yu, S., Hall, H.S., Kundra, V., Mills, G.B., and Sabbadini, R.A. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell, 9, 2006, 225–238.PubMedCrossRefGoogle Scholar
  161. Wang, G., Silva, J., Krishnamurthy, K., Tran, E., Condie, B.G., and Bieberich, E. Direct binding to ceramide activates protein kinase Czeta before the formation of a pro-apoptotic complex with PAR-4 in differentiating stem cells. J Biol Chem, 280, 2005, 26415–26424.PubMedCrossRefGoogle Scholar
  162. Wang, H., Maurer, B.J., Reynolds, C.P., and Cabot, M.C. N-(4-hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase. Cancer Res, 61, 2001, 5102–5105.PubMedGoogle Scholar
  163. Wolff, R.A., Dobrowsky, R.T., Bielawska, A., Obeid, L.M., and Hannun, Y.A. Role of ceramide-activated protein phosphatase in ceramide-mediated signal transduction. J Biol Chem, 269, 1994, 19605–19609.PubMedGoogle Scholar
  164. Wooten-Blanks, L.G., Song, P., Senkal, C.E., and Ogretmen, B. Mechanisms of ceramide-mediated repression of the human telomerase reverse transcriptase promoter via deacetylation of Sp3 by histone deacetylase 1. Faseb J, 21, 2007, 3386–3397.PubMedCrossRefGoogle Scholar
  165. Wooten, L.G. and Ogretmen, B. Sp1/Sp3-dependent regulation of human telomerase reverse transcriptase promoter activity by the bioactive sphingolipid ceramide. J Biol Chem, 280, 2005, 28867–28876.PubMedCrossRefGoogle Scholar
  166. Xia, P., Gamble, J.R., Wang, L., Pitson, S.M., Moretti, P.A., Wattenberg, B.W., D'Andrea, R.J., and Vadas, M.A. An oncogenic role of sphingosine kinase. Curr Biol, 10, 2000, 1527–1530.PubMedCrossRefGoogle Scholar
  167. Zhang, P., Liu, B., Jenkins, G.M., Hannun, Y.A., and Obeid, L.M. Expression of neutral sphingomyelinase identifies a distinct pool of sphingomyelin involved in apoptosis. J Biol Chem, 272, 1997, 9609–9612.PubMedCrossRefGoogle Scholar
  168. Zheng, W., Kollmeyer, J., Symolon, H., Momin, A., Munter, E., Wang, E., Kelly, S., Allegood, J.C., Liu, Y., Peng, Q., Ramaraju, H., Sullards, M.C., Cabot, M., and Merrill, A.H., Jr. Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim Biophys Acta, 1758, 2006, 1864–1884.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Sahar A. Saddoughi
  • Pengfei Song
  • Besim Ogretmen
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, Hollings Cancer CenterMedical University of South Carolina, Medical University of South CarolinaCharlestonUSA

Personalised recommendations