Cancer Treatment Strategies Targeting Sphingolipid Metabolism

Abstract

Ceramide and sphingosine-1-phosphate are related sphingolipid metabolites that can be generated through a de novo biosynthetic route or derived from the recycling of membrane sphingomyelin. Both these lipids regulate cellular responses to stress, with generally opposing effects. Sphingosine-1-phosphate functions as a growth and survival factor, acting as a ligand for a family of G protein-coupled receptors, whereas ceramide activates intrinsic and extrinsic apoptotic pathways through receptor-independent mechanisms. A growing body of evidence has implicated ceramide, sphingosine-1-phosphate and the genes involved in their synthesis, catabolism and signaling in various aspects of oncogenesis, cancer progression and drug- and radiation resistance. This may be explained in part by the finding that both lipids impinge upon the PI3K/AKT pathway, which represses apoptosis and autophagy. In addition, sphingolipids influence cell cycle progression, telomerase function, cell migration and stem cell biology. Considering the central role of ceramide in mediating physiological as well as pharmacologically stimulated apoptosis, ceramide can be considered a tumor-suppressor lipid. In contrast, sphingosine-1-phosphate can be considered a tumor-promoting lipid, and the enzyme responsible for its synthesis functions as an oncogene. Not surprisingly, genetic mutations that result in reduced ceramide generation, increased sphingosine-1-phosphate synthesis or which reduce steady state ceramide levels and increase sphingosine-1-phosphate levels have been identified as mechanisms of tumor progression and drug resistance in cancer cells. Pharmacological tools for modulating sphingolipid pathways are being developed and represent novel therapeutic strategies for the treatment of cancer.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Morales A, Lee H, Goñi F et al. Sphingolipids and cell death. Apoptosis 2007; 12:923–39.PubMedGoogle Scholar
  2. 2.
    Futerman A, Riezman H. The ins and outs of sphingolipid synthesis. Trends Cell Biol 2005; 15:312–8.PubMedGoogle Scholar
  3. 3.
    Kihara A, Mitsutake S, Mizutani Y et al. Metabolism and biological functions of two phosphorylated sphingolipids, sphingosine 1-phosphate and ceramide 1-phosphate. Prog Lipid Res 2007; 46:126–44.PubMedGoogle Scholar
  4. 4.
    Prinetti A, Chigorno V, Mauri L et al. Modulation of cell functions by glycosphingolipid metabolic remodeling in the plasma membrane. J Neurochem 2007; 103(Suppl 1):113–25.PubMedGoogle Scholar
  5. 5.
    Zeidan Y, Hannun Y. Translational aspects of sphingolipid metabolism. Trends Mol Med 2007; 13:327–36.PubMedGoogle Scholar
  6. 6.
    Kitatani K, Idkowiak-Baldys J, Hannun YA. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 2007.Google Scholar
  7. 7.
    Murph M, GB M. Targeting the lipids LPA and S1P and their signalling pathways to inhibit tumour progression. Expert Rev Mol Med 2007; 9:1–18.PubMedGoogle Scholar
  8. 8.
    Kolesnick RN, Goni FM, Alonso A. Compartmentalization of ceramide signaling: physical foundations and biological effects. J Cell Physiol 2000; 184(3):285–300.PubMedGoogle Scholar
  9. 9.
    Itoh M, Kitano T, Watanabe M et al. Possible role of ceramide as an indicator of chemoresistance: decrease of the ceramide content via activation of glucosylceramide synthase and sphingomyelin synthase in chemoresistant leukemia. Clin Cancer Res 2003; 9(1):415–23.PubMedGoogle Scholar
  10. 10.
    Okazaki T, Bell R, Hannun Y. Sphingomyelin turnover induced by vitamin D3 in HL-60 cells. J Biol Chem 1989; 264(32):19076–80.PubMedGoogle Scholar
  11. 11.
    Liu B, Obeid L, Hannun Y. Sphingomyelinases in cell regulation. Semin Cell Dev Biol 1998; 8(3):311–22.Google Scholar
  12. 12.
    Valaperta R, Chigorno V, Basso L et al. Plasma membrane production of ceramide from ganglioside GM3 in human fibroblasts. FASEB J 2006; 20:1227–9.PubMedGoogle Scholar
  13. 13.
    Nikolova-Karakashian M, Merril AH Jr. Ceramidases. Methods Enzymol 2000; 311(Part A):194–207.PubMedGoogle Scholar
  14. 14.
    Olivera A, Spiegel S. Sphingosine kinase: a mediator of vital cellular functions. Prostaglandins Other Lipid Mediat 2001; 64(1–4):123–34.PubMedGoogle Scholar
  15. 15.
    Le Stunff H, Peterson C, Liu H et al. Sphingosine-1-phosphate and lipid phosphohydrolases. Biochim Biophys Acta 2002; 1582(1–3):8–17.PubMedGoogle Scholar
  16. 16.
    Mandala SM, Thornton R, Tu Z et al. Sphingoid base 1-phosphate phosphatase: a key regulator of sphingolipid metabolism and stress response. Proc Natl Acad Sci USA 1998; 95(1):150–5.PubMedGoogle Scholar
  17. 17.
    Bandhuvula P, Saba J. Sphingosine-1-phosphate lyase in immunity and cancer: silencing the siren. Trends Mol Med 2007; 13(5):210–7.PubMedGoogle Scholar
  18. 18.
    Watanabe M, Kitano T, Kondo T et al. Increase of nuclear ceramide through caspase-3-dependent regulation of the “sphingomyelin cycle” in Fas-induced apoptosis. Cancer Res 2004; 64(3):1000–7.PubMedGoogle Scholar
  19. 19.
    Clarke C, Snook C, Tani M et al. The extended family of neutral sphingomyelinases. Biochemistry 2006; 45:11247–56.PubMedGoogle Scholar
  20. 20.
    Jayadev S, Liu B, Bielawska A et al. Role for ceramide in cell cycle arrest. J Biol Chem 1995; 270(5):2047–52.PubMedGoogle Scholar
  21. 21.
    Yoshimura S, Banno Y, Nakashima S et al. Ceramide formation leads to caspase-3 activation during hypoxic PC12 cell death. Inhibitory effects of Bcl-2 on ceramide formation and caspase-3 activation. J Biol Chem 1998; 273(12):6921–7.PubMedGoogle Scholar
  22. 22.
    Liu Y, Wada R, Yamashita T et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 2000; 106(8):951–61.PubMedGoogle Scholar
  23. 23.
    Takeda Y, Tashima M, Takahashi A et al. Ceramide generation in nitric oxide-induced apoptosis. Activation of magnesium-dependent neutral sphingomyelinase via caspase-3. J Biol Chem 1999; 274(15):10654–60.PubMedGoogle Scholar
  24. 24.
    Mansat V, Laurent G, Levade T et al. The protein kinase C activators phorbol esters and phosphatidylserine inhibit neutral sphingomyelinase activation, ceramide generation and apoptosis triggered by daunorubicin. Cancer Res 1997; 57(23):5300–4.PubMedGoogle Scholar
  25. 25.
    Sawada M, Nakashima S, Banno Y et al. Ordering of ceramide formation, caspase activation and Bax/Bcl-2 expression during etoposide-induced apoptosis in C6 glioma cells. Cell Death Differ 2000; 7(9):761–72.PubMedGoogle Scholar
  26. 26.
    Hara S, Nakashima S, Kiyono T et al. p53-Independent ceramide formation in human glioma cells during gamma-radiation-induced apoptosis. Cell Death Differ 2004; 11:853–61.PubMedGoogle Scholar
  27. 27.
    Jayadev S, Linardic C, Hannun Y. Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to tumor necrosis factor a. J Biol Chem 1994; 269(8):5757–63.PubMedGoogle Scholar
  28. 28.
    Schütze S, Machleidt T, Krönke M. The role of diacylglycerol and ceramide in tumor necrosis factor and interleukin-1 signal transduction. J Leukoc Biol 1994; 56:533–41.PubMedGoogle Scholar
  29. 29.
    Lei X, Zhang S, Bohrer A et al. The group VIA calcium-independent phospholipase A2 participates in ER stress-induced INS-1 insulinoma cell apoptosis by promoting ceramide generation via hydrolysis of sphingomyelins by neutral sphingomyelinase. Biochemistry 2007; 46:10170–85.PubMedGoogle Scholar
  30. 30.
    Bruno A, Laurent G, Averbeck D et al. Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation. Cell Death Differ 1998; 5:172–82.PubMedGoogle Scholar
  31. 31.
    Maddens S, Charruyer A, Plo I et al. Kit signaling inhibits the sphingomyelin-ceramide pathway through PLC gamma 1: implication in stem cell factor radioprotective effect. Blood 2002; 100:1294–301.PubMedGoogle Scholar
  32. 32.
    Liu B, Hannun Y. Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione. J Biol Chem 1997; 272:16281–7.PubMedGoogle Scholar
  33. 33.
    Marchesini N, Hannun Y. Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol 2004; 82:27–44.PubMedGoogle Scholar
  34. 34.
    Schneider PB, Kennedy EP. Sphingomyelinase in normal human spleens and in spleens from subjects with Niemann-Pick disease. J Lipid Res 1967; 8(3):202–9.PubMedGoogle Scholar
  35. 35.
    Santana P, Pena L, Haimovitz-Friedman A et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 1996; 86:189–99.PubMedGoogle Scholar
  36. 36.
    Zundel W, Giaccia A. Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress. Genes Dev 1998; 12(13):1941–6.PubMedGoogle Scholar
  37. 37.
    Schutze S, Potthoff K, Machleidt T et al. TNF activates NF-kB by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 1992; 71:765–76.PubMedGoogle Scholar
  38. 38.
    Kashkar H, Wiegmann K, Yazdanpanah B et al. Acid sphingomyelinase is indispensable for UV light-induced Bax conformational change at the mitochondrial membrane. J Biol Chem 2005; 280(21):20804–13.PubMedGoogle Scholar
  39. 39.
    Yu ZF, Nikolova-Karakashian M, Zhou D et al. Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production and neuronal apoptosis. J Mol Neurosci 2000; 15(2):85–97.PubMedGoogle Scholar
  40. 40.
    Schissel S, Keesler G, Schuchman E et al. The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene. J Biol Chem 1998; 273:18250–9.PubMedGoogle Scholar
  41. 41.
    Sathishkumar S, Boyanovsky B, Karakashian AA et al. Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: implications for endothelial apoptosis. Cancer Biol Ther 2005; 4(9):979–86.PubMedGoogle Scholar
  42. 42.
    Wright K, Messing E, Reeder J. Increased expression of the acid sphingomyelinase-like protein ASML3a in bladder tumors. J Urol 2002; 168:2645–9.PubMedGoogle Scholar
  43. 43.
    Nilsson A. The presence of spingomyelin-and ceramide-cleaving enzymes in the small intestinal tract. Biochim Biophys Acta 1969; 176(2):339–47.PubMedGoogle Scholar
  44. 44.
    Duan RD. Alkaline sphingomyelinase: an old enzyme with novel implications. Biochim Biophys Acta 2006; 1761(3):281–91.PubMedGoogle Scholar
  45. 45.
    Duan RD. Anticancer compounds and sphingolipid metabolism in the colon. In Vivo 2005; 19(1):293–300.PubMedGoogle Scholar
  46. 46.
    Bose R, Verheij M, Haimovitz-Friedman A et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 1995; 82(3):405–14.PubMedGoogle Scholar
  47. 47.
    Son JH, Yoo HH, Kim DH. Activation of de novo synthetic pathway of ceramides is responsible for the initiation of hydrogen peroxide-induced apoptosis in HL-60 cells. J Toxicol Environ Health A 2007; 70(15–16):1310–8.PubMedGoogle Scholar
  48. 48.
    Petrache I, Natarajan V, Zhen L et al. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat Med 2005; 11:491–8.PubMedGoogle Scholar
  49. 49.
    Turpin S, Lancaster G, Darby I et al. Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance. Am J Physiol Endocrinol Metab 2006; 291:E1341–350.Google Scholar
  50. 50.
    Itoh G, Tamura J, M S et al. DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis. Am J Pathol 1995; 146:1325–31.PubMedGoogle Scholar
  51. 51.
    Seumois G, Fillet M, Gillet L et al. De novo C16-and C24-ceramide generation contributes to spontaneous neutrophil apoptosis. J Leukoc Biol 2007; 81:1477–86.PubMedGoogle Scholar
  52. 52.
    Itoh Y, Yano T, Sendo T et al. Involvement of de novo ceramide synthesis in radiocontrast-induced renal tubular cell injury. Kidney Int 2006; 69:288–97.PubMedGoogle Scholar
  53. 53.
    Moussavi M, Assi K, Gomez-Munoz A et al. Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells. Carcinogenesis 2006; 27(8):1636–44.PubMedGoogle Scholar
  54. 54.
    Signorelli P, Ghidoni R. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 2005; 16:449–66.PubMedGoogle Scholar
  55. 55.
    Scarlatti F, Sala G, Somenzi G et al. Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. FASEB J 2003; 17(15):2339–41.PubMedGoogle Scholar
  56. 56.
    Chan T, Morin P, Vogelstein B et al. Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc Natl Acad Sci USA 1998; 95:681–6.PubMedGoogle Scholar
  57. 57.
    Ruvolo PP, Clark W, Mumby M et al. A functional role for the B56 alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function. J Biol Chem 2002; 277(25):22847–52.PubMedGoogle Scholar
  58. 58.
    Stoica BA, Movsesyan VA, Lea PMt et al. Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3beta and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci 2003; 22(3):365–82.PubMedGoogle Scholar
  59. 59.
    von Haefen C, Wieder T, Gillissen B et al. Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 2002; 21(25):4009–19.Google Scholar
  60. 60.
    Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene 2003; 22(37):5897–906.PubMedGoogle Scholar
  61. 61.
    Scorrano L, Oakes SA, Opferman JT et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis.Science 2003; 300(5616):135–9.PubMedGoogle Scholar
  62. 62.
    Kim HJ, Mun JY, Chun YJ et al. Bax-dependent apoptosis induced by ceramide in HL-60 cells. FEBS Lett 2001; 505(2):264–8.PubMedGoogle Scholar
  63. 63.
    Boise L, González-García M, Postema C et al. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993; 74:579–608.Google Scholar
  64. 64.
    Chalfant C, Rathman K, Pinkerman R et al. 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 2002; 277:12587–95.PubMedGoogle Scholar
  65. 65.
    Heinrich M, Wickel M, Schneider-Brachert W et al. Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J 1999; 18(19):5252–63.PubMedGoogle Scholar
  66. 66.
    Heinrich M, Neumeyer J, Jakob M et al. Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and-3 activation. Cell Death Differ 2004; 11(5):550–63.PubMedGoogle Scholar
  67. 67.
    Grassme H, Jekle A, Riehle A et al. CD95 signaling via ceramide-rich membrane rafts. J Biol Chem 2001; 276(23):20589–96.PubMedGoogle Scholar
  68. 68.
    Kilkus J, Goswami R, Testai FD et al. Ceramide in rafts (detergent-insoluble fraction) mediates cell death in neurotumor cell lines. J Neurosci Res 2003; 72(1):65–75.PubMedGoogle Scholar
  69. 69.
    Spiegel S, AH Merrill J. Sphingolipid metabolism and cell growth regulation. FASEB J 1996; 10:1388–97.PubMedGoogle Scholar
  70. 70.
    Yatomi Y, Ohmori T, Rile G et al. Sphingosine 1-phosphate as a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells. Blood 2000; 96(10):3431–8.PubMedGoogle Scholar
  71. 71.
    Radeff-Huang J, Seasholtz TM, Matteo RG et al. G protein mediated signaling pathways in lysophospholipid induced cell proliferation and survival. J Cell Biochem 2004; 92(5):949–66.PubMedGoogle Scholar
  72. 72.
    Hobson JP, Rosenfeldt HM, Barak LS et al. Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science 2001; 291(5509):1800–3.PubMedGoogle Scholar
  73. 73.
    Brinkmann V, Cyster J, Hla T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant 2004; 4:1019–25.PubMedGoogle Scholar
  74. 74.
    Spiegel S, Milstien S. Functions of a new family of sphingosine-1-phosphate receptors. Biochim Biophys Acta 2000; 1484(2–3):107–16.PubMedGoogle Scholar
  75. 75.
    Hla T, Lee MJ, Ancellin N et al. Lysophospholipids-receptor revelations. Science 2001; 294(5548):1875–8.PubMedGoogle Scholar
  76. 76.
    Payne SG, Milstien S, Spiegel S. Sphingosine-1-phosphate: dual messenger functions. FEBS Lett 2002; 531(1):54–7.PubMedGoogle Scholar
  77. 77.
    Xia P, Gamble JR, Wang L et al. An oncogenic role of sphingosine kinase. Curr Biol 2000; 10(23):1527–30.PubMedGoogle Scholar
  78. 78.
    Visentin B, Vekich J, Sibbald B et al. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion and angiogenesis in multiple tumor lineages. Cancer Cell 2006; 9:225–38.PubMedGoogle Scholar
  79. 79.
    Cuvillier O, Levade T. Sphingosine 1-phosphate antagonizes apoptosis of human leukemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria. Blood 2001; 98:2828–36.PubMedGoogle Scholar
  80. 80.
    Goetzl E, Kong Y, Mei B. Lysophosphatidic acid and sphingosine 1-phosphate protection of T-cells from apoptosis in association with suppression of Bax. J Immunol 1999; 162(4):2049–56.PubMedGoogle Scholar
  81. 81.
    Cuvillier O, Rosenthal DS, Smulson ME et al. Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas-and ceramide-mediated apoptosis in Jurkat T-lymphocytes. J Biol Chem 1998; 273(5):2910–6.PubMedGoogle Scholar
  82. 82.
    Betito S, Cuvillier O. Regulation by sphingosine 1-phosphate of Bax and Bad activities during apoptosis in a MEK-dependent manner. Biochem Biophys Res Commun 2006; 340(4):1273–7.PubMedGoogle Scholar
  83. 83.
    Taha TA, Kitatani K, Bielawski J et al. Tumor necrosis factor induces the loss of sphingosine kinase-1 by a cathepsin B-dependent mechanism. J Biol Chem 2005; 280(17):17196–202.PubMedGoogle Scholar
  84. 84.
    Liu H, Toman RE, Goparaju S et al. Sphingosine kinase type 2 is a putative BH3-Only protein that induces apoptosis. J Biol Chem 2003; 278:40330–6.PubMedGoogle Scholar
  85. 85.
    Le Stunff H, Giussani P, Maceyka M et al. Recycling of sphingosine is regulated by the concerted actions of sphingosine-1-phosphate phosphohydrolase 1 and sphingosine kinase 2. J Biol Chem 2007; 282:34372–80.PubMedGoogle Scholar
  86. 86.
    Spiegel S, Milstien S. Functions of the multifaceted family of sphingosine kinases and some close relatives. J Biol Chem 2006.Google Scholar
  87. 87.
    Woodgett JR. Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol 2005; 17(2):150–7.PubMedGoogle Scholar
  88. 88.
    Ruggero D, Sonenberg N. The Akt of translational control. Oncogene 2005; 24(50):7426–34.PubMedGoogle Scholar
  89. 89.
    Tohma Y, Gratas C, Biernat W et al. PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol 1998; 57(7):684–9.PubMedGoogle Scholar
  90. 90.
    Carpten JD, Faber AL, Horn C et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007; 448(7152):439–44.PubMedGoogle Scholar
  91. 91.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2(7):489–501.PubMedGoogle Scholar
  92. 92.
    Fox TE, Houck KL, O’Neill SM et al. Ceramide recruits and activates protein kinase C zeta (PKC zeta) within structured membrane microdomains. J Biol Chem 2007; 282(17):12450–7.PubMedGoogle Scholar
  93. 93.
    Powell DJ, Hajduch E, Kular G et al. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol Cell Biol 2003; 23(21):7794–808.PubMedGoogle Scholar
  94. 94.
    Salinas M, Lopez-Valdaliso R, Martin D et al. Inhibition of PKB/Akt1 by C2-ceramide involves activation of ceramide-activated protein phosphatase in PC12 cells. Mol Cell Neurosci 2000; 15(2):156–69.PubMedGoogle Scholar
  95. 95.
    Stratford S, Hoehn K, Liu F et al. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem 2004; 279:36608–15.PubMedGoogle Scholar
  96. 96.
    Law B, Rossie S. The dimeric and catalytic subunit forms of protein phosphatase 2A from rat brain are stimulated by C2-ceramide. J Biol Chem 1995; 270(21):12808–13.PubMedGoogle Scholar
  97. 97.
    Dobrowsky R, Kamibayashi C, Mumby M et al. Ceramide activates a heterotrimeric protein phosphatase 2A. J Biol Chem 1993; 268(21):15523–30.PubMedGoogle Scholar
  98. 98.
    Dey R, Majumder N, Bhattacharjee S et al. Leishmania donovani-induced ceramide as the key mediator of Akt dephosphorylation in murine macrophages: role of protein kinase Czeta and phosphatase. Infect Immun 2007; 75:2136–42.PubMedGoogle Scholar
  99. 99.
    Schmitz-Peiffer C, Craig D, Biden T. Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem 1999; 274:24202–10.PubMedGoogle Scholar
  100. 100.
    Guan L, Song K, Pysz M et al. Protein kinase C-mediated down-regulation of cyclin D1 involves activation of the translational repressor 4E-BP1 via a phosphoinositide 3-kinase/Akt-independent, protein phosphatase 2A-dependent mechanism in intestinal epithelial cells. J Biol Chem 2007; 282:14213–25.PubMedGoogle Scholar
  101. 101.
    Goswami R, Singh D, Phillips G et al. Ceramide regulation of the tumor suppressor phosphatase PTEN in rafts isolated from neurotumor cell lines. J Neurosci Res 2005; 81:541–50.PubMedGoogle Scholar
  102. 102.
    Gómez-Muñoz A, Kong J, Parhar K et al. Ceramide-1-phosphate promotes cell survival through activation of the phosphatidylinositol 3-kinase/protein kinase B pathway. FEBS Lett 2005; 579:3744–50.PubMedGoogle Scholar
  103. 103.
    Means C, Xiao C, Li Z et al. Sphingosine 1-phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2007; 292:H2944–H2951.PubMedGoogle Scholar
  104. 104.
    Igarashi J, Bernier SG, Michel T. Sphingosine 1-phosphate and activation of endothelial nitric-oxide synthase. differential regulation of Akt and MAP kinase pathways by EDG and bradykinin receptors in vascular endothelial cells. J Biol Chem 2001; 276(15):12420–6.PubMedGoogle Scholar
  105. 105.
    Levine Y, Li G, Michel T. Agonist-modulated regulation of AMP-activated protein kinase (AMPK) in endothelial cells. Evidence for an AMPK → Rac1 → Akt → endothelial nitric-oxide synthase pathway. J Biol Chem 2007; 282:20351–64.PubMedGoogle Scholar
  106. 106.
    Fieber C, Eldgridge J, Taha T et al. Modulation of total Akt kinase by increased expression of a single isoform: requirement of the sphingosine-1-phosphate receptor Edg3/S1P3, for the VEGF-dependent expression of Akt3 in primary endothelial cells. Exp Cell Res 2006; 312:1164–73.PubMedGoogle Scholar
  107. 107.
    Tanimoto T, Jin ZG, Berk BC. Transactivation of vascular endothelial growth factor (VEGF) receptor Flk-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). J Biol Chem 2002; 277(45):42997–3001.PubMedGoogle Scholar
  108. 108.
    Limaye V, Li X, Hahn C et al. Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1-dependent activation of PI-3K/Akt and regulation of Bcl-2 family members. Blood 2005; 105:3169–77.PubMedGoogle Scholar
  109. 109.
    Banno Y, Takuwa Y, Akao Y et al. Involvement of phospholipase D in sphingosine 1-phosphate-induced activation of phosphatidylinositol 3-kinase and Akt in Chinese hamster ovary cells overexpressing EDG3. J Biol Chem 2001; 276:35622–8.PubMedGoogle Scholar
  110. 110.
    Igarashi J, Michel T. Sphingosine 1-phosphate and isoform-specific activation of phosphoinositide 3-kinase beta. Evidence for divergence and convergence of receptor-regulated endothelial nitric-oxide synthase signaling pathways. J Biol Chem 2001; 276:36281–8.PubMedGoogle Scholar
  111. 111.
    Baudhuin LM, Jiang Y, Zaslavsky A et al. S1P3-mediated Akt activation and cross-talk with platelet-derived growth factor receptor (PDGFR). Faseb J 2004; 18(2):341–3.PubMedGoogle Scholar
  112. 112.
    Baudhuin L, Cristina K, Lu J et al. Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific. Mol Pharmacol 2002; 62:660–71.PubMedGoogle Scholar
  113. 113.
    Sanchez T, Skoura A, Wu M et al. Induction of vascular permeability by the sphingosine-1-phosphate receptor-2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler Thromb Vasc Biol 2007; 27:1312–8.PubMedGoogle Scholar
  114. 114.
    Liang C, Feng P, Ku B et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 2006; 8:688–99.PubMedGoogle Scholar
  115. 115.
    Mizushima N. Autophagy: process and function. Genes Dev 2007; 21(22):2861–73.PubMedGoogle Scholar
  116. 116.
    Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124(3):471–84.PubMedGoogle Scholar
  117. 117.
    Takeuchi H, Kondo Y, Fujiwara K et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 2005; 65(8):3336–46.PubMedGoogle Scholar
  118. 118.
    Scarlatti F, Bauvy C, Ventruti A et al. Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem 2004; 279:18384–91.PubMedGoogle Scholar
  119. 119.
    Patschan S, Chen J, Polotskaia A et al. Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells. Am J Physiol Heart Circ Physiol 2008; 294:H1119–H29.PubMedGoogle Scholar
  120. 120.
    Daido S, Kanzawa T, Yamamoto A et al. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 2004; 64(12):4286–93.PubMedGoogle Scholar
  121. 121.
    Lavieu G, Scarlatti F, Sala G et al. Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation. J Biol Chem 2006; 281:8518–27.PubMedGoogle Scholar
  122. 122.
    Boya P, Gonzalez-Polo RA, Casares N et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 2005; 25(3):1025–40.PubMedGoogle Scholar
  123. 123.
    Verheij M, Bose R, Lin X et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 1996; 380:75–9.PubMedGoogle Scholar
  124. 124.
    Basu S, Bayoumy S, Zhang Y et al. BAD enables ceramide to signal apoptosis via Ras and Raf-1. J Biol Chem 1998; 273(46):30419–26.PubMedGoogle Scholar
  125. 125.
    Cuvillier O, Pirianov G, Kleuser B et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 1996; 381(6585):800–3.PubMedGoogle Scholar
  126. 126.
    Edsall LC, Cuvillier O, Twitty S et al. Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. J Neurochem 2001; 76(5):1573–84.PubMedGoogle Scholar
  127. 127.
    Usui S, Sugimoto N, Takuwa N et al. Blood lipid mediator sphingosine 1-phosphate potently stimulates platelet-derived growth factor-A and-B chain expression through S1P1-Gi-Ras-MAPK-dependent induction of Kruppel-like factor 5. J Biol Chem 2004; 279(13):12300–11.PubMedGoogle Scholar
  128. 128.
    Hsieh HL, Sun CC, Wu CB et al. Sphingosine 1-phosphate induces EGFR expression via Akt/NF-kappaB and ERK/AP-1 pathways in rat vascular smooth muscle cells. J Cell Biochem 2007.Google Scholar
  129. 129.
    Libermann TA, Nusbaum HR, Razon N et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 1985; 313(5998):144–7.PubMedGoogle Scholar
  130. 130.
    Kohler M, Janz I, Wintzer HO et al. The expression of EGF receptors, EGF-like factors and c-myc in ovarian and cervical carcinomas and their potential clinical significance. Anticancer Res 1989; 9(6):1537–47.PubMedGoogle Scholar
  131. 131.
    Yoshida K, Tosaka A, Takeuchi S et al. Epidermal growth factor receptor content in human renal cell carcinomas. Cancer 1994; 73(7):1913–8.PubMedGoogle Scholar
  132. 132.
    Dbaibo G, Pushkareva M, Jayadev S et al. Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest. Proc Natl Acad Sci USA 1995; 92:1347–51.PubMedGoogle Scholar
  133. 133.
    Phillips DC, Hunt JT, Moneypenny CG et al. Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression. Cell Death Differ 2007; 14(10):1780–91.PubMedGoogle Scholar
  134. 134.
    Wang J, Lv XW, Shi JP et al. Mechanisms involved in ceramide-induced cell cycle arrest in human hepatocarcinoma cells. World J Gastroenterol 2007; 13(7):1129–34.PubMedGoogle Scholar
  135. 135.
    Blackburn EH, Greider CW, Szostak JW. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 2006; 12(10):1133–8.PubMedGoogle Scholar
  136. 136.
    Greider CW, Blackburn EH. Telomeres, telomerase and cancer. Sci Am 1996; 274(2):92–7.PubMedGoogle Scholar
  137. 137.
    Blackburn EH, Greider CW, Henderson E et al. Recognition and elongation of telomeres by telomerase. Genome 1989; 31(2):553–60.PubMedGoogle Scholar
  138. 138.
    Weinrich SL, Pruzan R, Ma L et al. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet 1997; 17(4):498–502.PubMedGoogle Scholar
  139. 139.
    Ogretmen B, Kraveka JM, Schady D et al. Molecular mechanisms of ceramide-mediated telomerase inhibition in the A549 human lung adenocarcinoma cell line. J Biol Chem 2001; 276(35):32506–14.PubMedGoogle Scholar
  140. 140.
    Wooten-Blanks LG, Song P, Senkal CE et al. Mechanisms of ceramide-mediated repression of the human telomerase reverse transcriptase promoter via deacetylation of Sp3 by histone deacetylase 1. FASEB J 2007; 21(12):3386–97.PubMedGoogle Scholar
  141. 141.
    Xu JX, Morii E, Liu Y et al. High tolerance to apoptotic stimuli induced by serum depletion and ceramide in side-population cells: high expression of CD55 as a novel character for side-population. Exp Cell Res 2007; 313(9):1877–85.PubMedGoogle Scholar
  142. 142.
    Ozaki H, Hla T, Lee MJ. Sphingosine-1-phosphate signaling in endothelial activation. J Atheroscler Thromb 2003; 10(3):125–31.PubMedGoogle Scholar
  143. 143.
    Park KS, Kim MK, Lee HY et al. S1P stimulates chemotactic migration and invasion in OVCAR3 ovarian cancer cells. Biochem Biophys Res Commun 2007; 356(1):239–44.PubMedGoogle Scholar
  144. 144.
    Guo XZ, Zhang WW, Wang LS et al. [Adenovirus-mediated overexpression of KAI1 suppresses sphingosine kinase activation and metastasis of pancreatic carcinoma cells]. Zhonghua Nei Ke Za Zhi 2006; 45(9):752–4.PubMedGoogle Scholar
  145. 145.
    Selzner M, Bielawska A, Morse MA et al. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res 2001; 61(3):1233–40.PubMedGoogle Scholar
  146. 146.
    Elojeimy S, Liu X, McKillop JC et al. Role of acid ceramidase in resistance to FasL: Therapeutic approaches based on acid ceramidase inhibitors and FasL gene therapy. Mol Ther 2007; 15(7):1259–63.PubMedGoogle Scholar
  147. 147.
    Holman DH, Turner LS, El-Zawahry A et al. Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells. Cancer Chemother Pharmacol 2008; 61(2):231–42.PubMedGoogle Scholar
  148. 148.
    Swanton C, Marani M, Pardo O et al. Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. Cancer Cell 2007; 11(6):498–512.PubMedGoogle Scholar
  149. 149.
    Kawamori T, Osta W, Johnson KR et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J 2006; 20(2):386–8.PubMedGoogle Scholar
  150. 150.
    Johnson KR, Johnson KY, Crellin HG et al. Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem 2005; 53(9):1159–66.PubMedGoogle Scholar
  151. 151.
    French K, Schrecengost R, Lee B et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 2003; 63:5962–9.PubMedGoogle Scholar
  152. 152.
    French K, Upson J, Keller S et al. Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther 2006; 318:596–603.PubMedGoogle Scholar
  153. 153.
    Le Scolan E, Pchejetski D, Banno Y et al. Overexpression of sphingosine kinase 1 is an oncogenic event in erythroleukemic progression. Blood 2005; 106(5):1808–16.PubMedGoogle Scholar
  154. 154.
    Kohno M, Momoi M, Oo M et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol 2006; 26:7211–23.PubMedGoogle Scholar
  155. 155.
    Oskouian B, Sooriyakumaran P, Borowsky A et al. Sphingosine-1-phosphate lyase potentiates apoptosis via p53-and p38-dependent pathways and is downregulated in colon cancer. Proc Natl Acad Sci USA 2006; 103:17384–9.PubMedGoogle Scholar
  156. 156.
    Symolon H, Schmelz E, Dillehay D et al. Dietary soy sphingolipids suppress tumorigenesis and gene expression in 1,2-dimethylhydrazine-treated CF1 mice and ApcMin/+ mice. J Nutr 2004; 134:1157–61.PubMedGoogle Scholar
  157. 157.
    Schmelz EM, Dillehay DL, Webb SK et al. 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 1996; 56(21):4936–41.PubMedGoogle Scholar
  158. 158.
    Schmelz EM, Roberts PC, Kustin EM et al. Modulation of intracellular beta-catenin localization and intestinal tumorigenesis in vivo and in vitro by sphingolipids. Cancer Res 2001; 61(18):6723–9.PubMedGoogle Scholar
  159. 159.
    Bonhoure E, Pchejetski D, Aouali N et al. Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1. Leukemia 2006; 20(1):95–102.PubMedGoogle Scholar
  160. 160.
    Bektas M, Jolly PS, Muller C et al. Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression. Oncogene 2005; 24(1):178–87.PubMedGoogle Scholar
  161. 161.
    Schindler T, Bornmann W, Pellicena P et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000; 289(5486):1938–42.PubMedGoogle Scholar
  162. 162.
    Baran Y, Salas A, Senkal CE et al. 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 2007; 282(15):10922–34.PubMedGoogle Scholar
  163. 163.
    Bittman R. Synthetic sphingolipids as bioactive molecules: roles in regulation of cell function. In: Wiley, editor. Wiley Encyclopedia 2008.Google Scholar
  164. 164.
    McCormack P, Goa K. Miglustat. Drugs 2003; 63:2427–36.PubMedGoogle Scholar
  165. 165.
    Weiss M, Hettmer S, Smith P et al. Inhibition of melanoma tumor growth by a novel inhibitor of glucosylceramide synthase. Cancer Res 2003; 63(13):3654–8.PubMedGoogle Scholar
  166. 166.
    Guerrera M, Ladisch S. N-butyldeoxynojirimycin inhibits murine melanoma cell ganglioside metabolism and delays tumor onset. Cancer Lett 2003; 201(1):31–40.PubMedGoogle Scholar
  167. 167.
    Dbaibo GS, Kfoury Y, Darwiche N et al. Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity. Haematologica 2007; 92(6):753–62.PubMedGoogle Scholar
  168. 168.
    Billich A, Bornancin F, Mechtcheriakova D et al. Basal and induced sphingosine kinase 1 activity in A549 carcinoma cells: function in cell survival and IL-1beta and TNF-alpha induced production of inflammatory mediators. Cell Signal 2005; 17:1203–17.PubMedGoogle Scholar
  169. 169.
    Gamble J, Xia P, Hahn C et al. Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects. Int J Cancer 2006; 118:2412–20.PubMedGoogle Scholar
  170. 170.
    Leroux M, Auzenne E, Evans R et al. Sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells. Prostate 2007; 67:1699–717.PubMedGoogle Scholar
  171. 171.
    Leroux ME, Auzenne E, Evans R et al. Sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells. Prostate 2007; 67(15):1699–717.PubMedGoogle Scholar
  172. 172.
    Yasui H, Hideshima T, Raje N et al. FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance. Cancer Res 2005; 65(16):7478–84.PubMedGoogle Scholar
  173. 173.
    Sani BP, Shealy YF, Hill DL. N-(4-hydroxyphenyl)retinamide: interactions with retinoid-binding proteins/ receptors. Carcinogenesis 1995; 16(10):2531–4.PubMedGoogle Scholar
  174. 174.
    Sheikh MS, Shao ZM, Li XS et al. N-(4-hydroxyphenyl)retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma. Carcinogenesis 1995; 16(10):2477–86.PubMedGoogle Scholar
  175. 175.
    Wang H, Maurer BJ, Reynolds CP et al. N-(4-hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase. Cancer Res 2001; 61(13):5102–5.PubMedGoogle Scholar
  176. 176.
    Maurer BJ, Melton L, Billups C et al. Synergistic cytotoxicity in solid tumor cell lines between N-(4-hydroxyphenyl)retinamide and modulators of ceramide metabolism. J Natl Cancer Inst 2000; 92(23):1897–909.PubMedGoogle Scholar
  177. 177.
    Erdreich-Epstein A, Tran LB, Bowman NN et al. Ceramide signaling in fenretinide-induced endothelial cell apoptosis. J Biol Chem 2002; 277(51):49531–7.PubMedGoogle Scholar
  178. 178.
    Kraveka J, Li L, Szulc Z et al. Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J Biol Chem 2007; 282:16718–28.PubMedGoogle Scholar
  179. 179.
    Jiang Q, Wong J, Fyrst H et al. gamma-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. Proc Natl Acad Sci USA 2004; 101(51):17825–30.PubMedGoogle Scholar
  180. 180.
    Morales PR, Dillehay DL, Moody SJ et al. Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation. Drug Chem Toxicol 2007; 30(3):197–216.PubMedGoogle Scholar
  181. 181.
    Grammatikos G, Teichgraber V, Carpinteiro A et al. Overexpression of acid sphingomyelinase sensitizes glioma cells to chemotherapy. Antioxid Redox Signal 2007; 9(9):1449–56.PubMedGoogle Scholar
  182. 182.
    Won JS, Singh I. Sphingolipid signaling and redox regulation. Free Radic Biol Med 2006; 40(11):1875–88.PubMedGoogle Scholar
  183. 183.
    Andersson D, Cheng Y, Duan RD. Ursolic acid inhibits the formation of aberrant crypt foci and affects colonic sphingomyelin hydrolyzing enzymes in azoxymethane-treated rats. J Cancer Res Clin Oncol 2008; 134(1):101–7.PubMedGoogle Scholar
  184. 184.
    Rosato RR, Maggio SC, Almenara JA et al. The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury and the acid sphingomyelinase-dependent generation of ceramide. Mol Pharmacol 2006; 69(1):216–25.PubMedGoogle Scholar
  185. 185.
    Darroch PI, Dagan A, Granot T et al. A lipid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide and leads to cell death. J Lipid Res 2005; 46(11):2315–24.PubMedGoogle Scholar
  186. 186.
    Suomalainen L, Hakala JK, Pentikainen V et al. Sphingosine-1-phosphate in inhibition of male germ cell apoptosis in the human testis. J Clin Endocrinol Metab 2003; 88(11):5572–9.PubMedGoogle Scholar
  187. 187.
    Pchejetski D, Kunduzova O, Dayon A et al. Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis. Circ Res 2007; 100(1):41–9.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Children’s Hospital Oakland Research InstituteOaklandUSA

Personalised recommendations