Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Sphingosine 1-phosphate and cancer

Key Points

  • Sphingosine 1-phosphate (S1P) is a biologically active lipid that promotes tumour growth, neovascularization and inflammation. It regulates the growth, survival and migration of mammalian cells through both intracellular and receptor-mediated mechanisms.

  • S1P is formed by the sphingosine kinase (SK)-catalysed phosphorylation of sphingosine. There are two isoforms of SK, SK1 and SK2.

  • SK1 promotes V12Ras-dependent transformation, and the growth and survival of cancer cells, while inhibiting apoptosis and conferring resistance to γ-irradiation and chemotherapeutic agents.

  • No mutations linked with cancer have been identified in SK1. However, cancer cells demonstrate a reliance on this enzyme for cell growth and survival, that is, a non-oncogenic addiction for SK1.

  • SK1 expression is increased in several types of human tumours compared with normal tissue and, in some cases, this is correlated with disease progression and reduced patient survival.

  • A ceramide–sphingosine–S1P rheostat exists in cells. Ceramide and sphingosine are pro-apoptotic, whereas S1P promotes cell survival. Agents that regulate the interconversion of ceramide–sphingosine–S1P can direct the cell towards either an apoptotic or a survival programme depending on the relative position of the rheostat.

  • The sensitivity of cancer cells to chemotherapeutic agents is a function of the activities of SK (which produces S1P) and S1P lyase and S1P phosphatases (which remove S1P).

  • S1P stimulates S1P-specific plasma membrane G protein-coupled receptors (S1PR1–5). S1PR1 and S1PR3 generally promote migration and cell survival, whereas S1PR2 is generally inhibitory for migration.

  • S1P receptors crosstalk with receptor tyrosine kinases to regulate tumorigenesis and neovascularization. This includes S1P-dependent transactivation of receptor tyrosine kinases, the formation of functional receptor tyrosine kinase–S1P receptor complexes and the amplification of regulatory loops.

  • Solid tumours are often oxygen insufficient and express hypoxia-inducible factors. In this regard, hypoxia increases SK1 and SK2 expression to promote neovascularization of the tumour.

  • Anticancer therapeutics in development include S1P-specific neutralizing antibodies (such as ASONEP), SK inhibitors and functional S1P receptor antagonists, which may mitigate the hyperproliferative, migratory and inflammatory components of cancer.

Abstract

There is substantial evidence that sphingosine 1-phosphate (S1P) is involved in cancer. S1P regulates processes such as inflammation, which can drive tumorigenesis; neovascularization, which provides cancer cells with nutrients and oxygen; and cell growth and survival. This occurs at multiple levels and involves S1P receptors, sphingosine kinases, S1P phosphatases and S1P lyase. This Review summarizes current research findings and examines the potential for new therapeutics designed to alter S1P signalling and function in cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: S1P receptors.
Figure 2: The ceramide–sphingosine–S1P rheostat, 'inside-out' signalling and cancer cell survival.
Figure 3: SK1 targeting to the plasma membrane.
Figure 4: Interaction between S1P and EGFR, and VEGFR2 and PDGFRβ.
Figure 5: Summary of the actions of S1P in cancer.

Similar content being viewed by others

References

  1. Pyne, S. & Pyne, N. J. Sphingosine 1-phosphate signalling in mammalian cells. Biochem. J. 349, 385–402 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Spiegel, S. & Milstien, S. Sphingosine 1-phosphate: an enigmatic signalling lipid. Nature Rev. Mol. Cell Biol. 4, 397–407 (2003).

    Article  CAS  Google Scholar 

  3. Ogretmen, B. & Hannun, Y. A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nature Rev. Cancer 4, 604–616 (2004).

    Article  CAS  Google Scholar 

  4. Hannun, Y. A. & Obeid, L. M. Principles of bioactive lipid signalling: lessons from sphingolipids. Nature Rev. Mol. Cell Biol. 9, 139–150 (2008).

    Article  CAS  Google Scholar 

  5. Xia, P. et al. An oncogenic role of sphingosine kinase. Curr. Biol. 10, 1527–1530 (2000). This paper reports the first demonstration that SK1 increases V12 RAS-dependent transformation of NIH3T3 fibroblasts to form fibrosarcoma cells.

    Article  CAS  PubMed  Google Scholar 

  6. Vadas, M., Xia, P., McCaughan, G. & Gamble, J. The role of sphingosine kinase-1 in cancer: oncogene or non-oncogene addiction. Biochim. Biophys. Acta 1781, 442–447 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Li, W. et al. Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients. Clin. Cancer Res. 15, 1393–1399 (2009). This paper describes clinical evidence for a role of SK1 in disease progression and reduced survival in patients with gastric cancer.

    Article  CAS  PubMed  Google Scholar 

  8. French, K. J. et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 63, 5962–5969 (2003). This paper identifies the first non-lipid inhibitors of SK.

    CAS  PubMed  Google Scholar 

  9. Johnson, K. R. et al. Immunohistochemical distribution of sphingosine kinase 1 in normal and tumour lung tissue. J. Histochem. Cytochem. 53, 1159–1166 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Li, J. et al. Clinical significance of sphingosine kinase-1 expression in human astrocytomas progression and overall patient survival. Clin. Cancer Res. 14, 6996–7003 (2008). This paper reports clinical evidence for a role of SK1 in disease progression and reduced survival in cancer patients with astocytoma.

    Article  CAS  PubMed  Google Scholar 

  11. Van Brocklyn, J. R. et al. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J. Neuropathol. Exp. Neurol. 64, 695–705 (2005). This paper describes clinical evidence for a role of SK1 in reducing the survival of patients with glioma.

    Article  CAS  PubMed  Google Scholar 

  12. Kohno, M. et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol. Cell. Biol. 26, 7211–7223 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kawamori, T. et al. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 23, 405–414 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bayerl, M. G. et al. Sphingosine kinase 1 protein and mRNA are overexpressed in non-Hodgkin lymphomas and are attractive targets for novel pharmacological interventions. Leuk. Lymphoma 49, 948–954 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Ruckäberle, E. et al. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res. Treat 112, 41–52 (2008). This reports clinical evidence for a role of SK1 in reducing the survival of patients with breast cancer.

    Article  CAS  Google Scholar 

  16. Erez-Roman, R., Pienik, R. & Futerman, A. H. Increased ceramide synthase 2 and 6 mRNA levels in breast cancer tissues and correlation with sphingosine kinase expression. Biochem. Biophys. Res. Commun. 391, 219–223 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Foekens, J. A. et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res. 60, 636–643 (2000).

    CAS  PubMed  Google Scholar 

  18. Muracciole, X. et al. PAI-1 and EGFR expression in adult glioma tumours: toward a molecular prognostic classification. Int. J. Radiat. Oncol. Biol. Phys. 52, 592–598 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Paugh, B. S. et al. EGF regulates plasminogen activator inhibitor-1 (PAI-1) by a pathway involving c-Src, PKCδ and sphingosine kinase 1 in glioblastoma cells. FASEB J. 22, 455–465 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Xu, Y., Xiao, Y. J., Baudhuin, L. M. & Schwartz, B. M. The role and clinical applications of bioactive lysolipids in ovarian cancer. J. Soc. Gynecol. Investig. 8, 1–13 (2001).

    Article  PubMed  Google Scholar 

  21. Wang, D. et al. S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells Mol. Cancer Ther. 7, 1993–2002 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sutphen, R. et al. Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol. Biomarkers Prev. 13, 1185–1191 (2004).

    CAS  PubMed  Google Scholar 

  23. Takabe, K., Paugh, S. W., Milstien, S. & Spiegel, S. 'Inside-out' signalling of sphingosine-1-phosphate: therapeutic targets. Pharmacol. Rev. 60, 181–195 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Visentin, B. et al. Validation of an anti-sphingosine 1-phosphate antibody as a potential therapeutic in reducing growth, invasion and angiogenesis in multiple tumour lineages. Cancer Cell 9, 225–238 (2006). A report of the new therapeutic development of an S1P-specific antibody that may have applications in preventing tumour growth and neovascularization.

    Article  CAS  PubMed  Google Scholar 

  25. Mitra, P. et al. Role of ABCC1 in export of sphingosine 1-phosphate from mast cells. Proc. Natl Acad. Sci. USA 103, 16394–16399 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sato, K. et al. Critical role of ABCA1 transporter in sphingosine 1-phosphate release from astrocytes. J. Neurochem. 103, 2610–2619 (2007).

    CAS  PubMed  Google Scholar 

  27. Takabe, K. et al. Estradiol induces export of sphingosine-1-phosphate from breast cancer cells via ABCC1 and ABCG2. J. Biol. Chem. 285, 10477–10486 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee, Y. M., Venkataraman, K., Hwang, S. I., Han, D. K. & Hla, T. A novel method to quantify sphingosine 1-phosphate by immobilized metal affinity chromatography (IMAC). Prostaglandins Other Lipid Mediat. 84, 154–162 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Osborne, N. et al. The spinster homolog, two of hearts, is required for sphingosine 1-phosphate signalling in zebrafish. Curr. Biol. 18, 1882–1888 (2008). This paper identifies an S1P transporter protein that is essential for the normal development of the zebrafish heart.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kawahara, A. et al. The sphingolipid transporter spns2 functions in migration of zebrafish myocardial precursors. Science 323, 524–527 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Taha, T. A., Hannun, Y. A. & Obeid, L. M. Sphingosine kinase: biochemical and cellular regulation and role in disease. J. Biochem. Mol. Biol. 39, 113–131 (2006).

    CAS  PubMed  Google Scholar 

  32. Alemany, R., van Koppen, C. J., Danneberg, K., Ter Braak, M. & Meyer Zu Heringdorf, D. Regulation and functional roles of sphingosine kinases. Naunyn Schmiedebergs Arch. Pharmacol. 374, 413–428 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Pyne, S., Lee, S. C., Long, J. & Pyne, N. J. Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease. Cell Signal. 21, 14–21 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Pitson, S. M. et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J. 22, 5491–5500 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pitson, S. M. et al. Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J. Exp. Med. 201, 49–54 (2005). This was the first study to show that the re-localization of SK1 from the cytoplasm to the plasma membrane of cells is required for the transformation of NIH3T3 fibroblasts to form fibrosarcoma cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stahelin, R. V. et al. The mechanism of membrane targeting of human sphingosine kinase 1. J. Biol. Chem. 280, 43030–43038 (2005). This paper identifies SK1–phosphatidylserine interaction at the plasma membrane.

    Article  CAS  PubMed  Google Scholar 

  37. Olivera, A., Rosenthal, J. & Spiegel, S. Effect of acidic phospholipids on sphingosine kinase. J. Cell. Biochem. 60, 529–537 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Su, W., Chen, Q. & Frohman, M. A. Targeting phospholipase D with small-molecule inhibitors as a potential therapeutic approach for cancer metastasis. Future. Oncol. 5, 1477–1486 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Melendez, A. J. & Khaw, A. K. Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells. J. Biol. Chem. 277, 17255–17262 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Smith, R. E. et al. A novel MyD-1 (SIRP-1α) signalling pathway that inhibits LPS-induced TNFα production by monocytes. Blood 102, 2532–2540 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Delon, C. et al. Sphingosine kinase 1 is an intracellular effector of phosphatidic acid. J. Biol. Chem. 279, 44763–44774 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Long, J. S. et al. The regulation of cell survival by lipid phosphate phosphatases involves the modulation of intracellular phosphatidic acid and sphingosine 1-phosphate pools. Biochem. J. 391, 25–32 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xia, P. et al. Sphingosine kinase interacts with TRAF2 and dissects tumour necrosis factor-α signalling. J. Biol. Chem. 277, 7996–8003 (2002). This was the first identification of a protein–protein interaction involving SK1.

    Article  CAS  PubMed  Google Scholar 

  44. Bergom, C., Gao, C. & Newman, P. J. Mechanisms of PECAM-1-mediated cytoprotection and implications for cancer cell survival. Leuk. Lymphoma 46, 1409–1421 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Limaye, V. 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 105, 3169–3177 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Maceyka, M., Nava, V. E., Milstien, S. & Spiegel, S. Aminoacylase 1 is a sphingosine kinase 1-interacting protein. FEBS Lett. 568, 30–34 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Zhong, Y. et al. Genome-wide analysis identifies a tumour suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. Carcinogenesis 30, 158–164 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Thornton, S., Anand, N., Purcell, D. & Lee, J. Not just for housekeeping: protein initiation and elongation factors in cell growth and tumourigenesis. J. Mol. Med. 81, 536–548 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Leclercq, T. M., Moretti, P. A., Vadas, M. A. & Pitson, S. M. Eukaryotic elongation factor 1A interacts with sphingosine kinase and directly enhances its catalytic activity. J. Biol. Chem. 283, 9606–9614 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jarman, K. E., Moretti, P. A., Zebol, J. R. & Pitson, S. M. Translocation of sphingosine kinase 1 to the plasma membrane is mediated by calcium- and integrin-binding protein 1. J. Biol. Chem. 285, 483–492 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Maceyka, M. et al. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J. Biol. Chem. 280, 37118–37129 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Igarashi, N. et al. Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J. Biol. Chem. 278, 46832–46839 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Ding, G. et al. Protein kinase D-mediated phosphorylation and nuclear export of sphingosine kinase 2. J. Biol. Chem. 282, 27493–27502 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Don, A. S. & Rosen, H. A lipid binding domain in sphingosine kinase 2. Biochem. Biophys. Res. Commun. 380, 87–92 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu, H. et al. Sphingosine kinase type 2 is a putative BH-3 only protein that induces apoptosis. J. Biol. Chem. 278, 40330–40336 (2003). First demonstration of the pro-apoptotic function of SK2.

    Article  CAS  PubMed  Google Scholar 

  56. Sankala, H. M. et al. Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin. Cancer Res. 67, 10466–10474 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Hait, N. C., Bellamy, A., Milstien, S., Kordula, T. & Spiegel. S. Sphingosine kinase type 2 activation by ERK-mediated phosphorylation. J. Biol. Chem. 282, 12058–12065 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Weigert, A. et al. Sphingosine kinase 2 deficient tumour xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotype. Int. J. Cancer. 125, 2114–2121 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Hait, N. C. et al. Regulation of histone acetylation in the nucleus by sphingosine 1-phosphate. Science 325, 1254–1257 (2009). This paper reports a novel interaction of S1P with the intracellular target HDAC regulating the epigenetic control of cell cycle progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Allende, M. L. et al. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J. Biol. Chem. 279, 52487–52492 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Mizugishi, M. et al. Essential role for sphingosine kinase in neural and vascular development. Mol. Cell. Biol. 25, 11113–11121 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cuvillier, O. et al. Suppression of ceramide-mediated programmed cell death by sphingosine 1-phosphate. Nature 381, 800–803 (1996). This was the first demonstration of the ceramide–sphingosine–S1P rheostat.

    Article  CAS  PubMed  Google Scholar 

  63. Heinrich, M. et al. Ceramide as an activator lipid of cathepsin D. Adv. Exp. Med. Biol. 477, 305–315 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, G. et al. Direct binding to ceramide activates protein kinase Cζ before the formation of a pro-apoptotic complex with PAR-4 in differentiating stem cells. J. Biol. Chem. 280, 26415–26424 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Fox, T. E. et al. Ceramide recruits and activates protein kinase C ζ (PKC ζ) within structured membrane microdomains. J. Biol. Chem. 282, 12450–12457 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Sauer, B. et al. Sphingosine 1-phosphate is involved in cytoprotective actions of calcitriol in human fibroblasts and enhances the intracellular Bcl-2/Bax rheostat. Pharmazie 60, 298–304 (2005).

    CAS  PubMed  Google Scholar 

  67. Li, Q. F., Wu, C. T., Guo, Q., Wang, H. & Wang, L. S. Sphingosine 1-phosphate induces Mcl-1 upregulation and protects multiple myeloma cells against apoptosis. Biochem. Biophys. Res. Commun. 371, 159–162 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Avery, K., Avery, S., Shepherd, J., Heath, P. R. & Moore, H. Sphingosine-1-phosphate mediates transcriptional regulation of key targets associated with survival, proliferation, and pluripotency in human embryonic stem cells. Stem Cells Dev. 17, 1195–1205 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. 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. 340, 1273–1277 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Jürgensmeier, J. M. et al. Bax directly induces release of cytochrome c from isolated mitochondria. Proc. Natl Acad. Sci. USA 95, 4997–5002 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Bonhoure, E. et al. Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukaemia cells. Leukemia 22, 971–979 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Bektas, M. et al. Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression. Oncogene 24, 178–187 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Akao, Y. et al. High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC-3 cells and their camptothecin-induced up-regulation. Biochem. Biophys. Res. Commun. 342, 1284–1290 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Pchejetski, D. et al. Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res. 65, 11667–11675 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Guillermet-Guibert, J. et al. Targeting the sphingolipid metabolism to defeat pancreatic cancer resistance to the chemotherapeutic gemcitabine drug. Mol. Cancer Res. 8, 809–820 (2009).

    CAS  Google Scholar 

  76. Baran, Y. et al. Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukaemia cells. J. Biol. Chem. 282, 10922–10934 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Sobue, S. et al. Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukaemia cells. Int. J. Haematol. 87, 266–275 (2008).

    Article  CAS  Google Scholar 

  78. Nava, V. E., Hobson, J. P., Murthy, S., Milstien, S. & Spiegel, S. Sphingosine kinase type 1 promotes estrogen-dependent tumourigenesis of breast cancer MCF-7 cells. Exp. Cell Res. 281, 115–127 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Kohno, M. et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol. Cell. Biol. 26, 7211–7223 (2006). This was the first identification of a potential intracellular role for SK1 in intestinal adenoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Pchejetski, D. et al. Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models. Mol. Cancer Ther. 7, 1836–1845 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Nava, V. E. et al. Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells. Cancer Res. 60, 4468–4474 (2000).

    CAS  PubMed  Google Scholar 

  82. Yamashita, H. et al. Sphingosine 1-phosphate receptor expression profile in human gastric cancer cells: differential regulation on the migration and proliferation. J. Surg. Res. 130, 80–87 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Arikawa, K. 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. 278, 32841–32851 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Yamamura, S., Hakomori, S., Wada, A. & Igarashi, Y. Sphingosine 1-phosphate inhibits haptotactic motility by overproduction of focal adhesion sites in B16 melanoma cells through EDG-induced activation of Rho. Ann. NY Acad. Sci. 905, 301–307 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Malchinkhuu, E. et al. S1P2 receptors mediate inhibition of glioma cell migration through Rho signalling pathways independent of PTEN. Biochem. Biophys. Res. Comm. 366, 963–968 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Sanchez, T. et al. Induction of vascular permeability by the sphingosine 1-phosphate receptor-2 (S1PR2) and its downstream effectors ROCK and PTEN. Atheroscler. Thromb. Vasc. Biol. 27, 1312–1318 (2007).

    Article  CAS  Google Scholar 

  87. Fisher, K. E. et al. Tumour cell invasion of collagen matrices requires coordinate lipid agonist-induced G protein and membrane-type matrix metalloproteinase-1-dependent signalling. Mol. Cancer 5, 69 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Nyalendo, C. et al. Src-dependent phosphorylation of membrane type I matrix metalloproteinase on cytoplasmic tyrosine 573: role in endothelial and tumour cell migration. J. Biol. Chem. 282, 15690–15699 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Park, K. S. et al. S1P stimulates chemotactic migration and invasion in OVCAR3 ovarian cancer cells. Biochem. Biophys. Res. Comm. 356, 239–244 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Young, N. & Van Brocklyn, J. R. Roles of sphingosine 1-phosphate (S1P) receptors in malignant behaviour of glioma cells. Differential effects of S1P2 on cell migration and invasiveness. Exp. Cell Res. 313, 1615–1627 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rodgers, A. et al. Sphingosine 1-phosphate regulation of extracellular signal-regulated kinase-1/2 in embryonic stem cells. Stem Cells Dev. 18, 1319–1330 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Yoshida, Y. et al. The expression level of sphingosine-1-phosphate receptor type 1 is related to MIB-1 labeling index and predicts survival of glioblastoma patients. J. Neurooncol. 98, 41–47 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Kothapalli, R., Kusmartseva, I. & Loughran, T. P. Characterization of a human sphingosine-1-phosphate receptor gene (S1P5) and its differential expression in LGL leukemia. Biochim. Biophys. Acta 1579, 117–123 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Cattoretti, G. et al. Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation. Cancer Res. 69, 8686–8692 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Le Stunff, H. et al. Role of sphingosine-1-phosphate phosphatase 1 in epidermal growth factor-induced chemotaxis. J. Biol. Chem. 279, 34290–34297 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Hsieh, H. L. et al. Sphingosine 1-phosphate induces EGFR expression via AKT/NF-κB and ERK/AP-1 pathways in rat vascular smooth muscle cells. J. Cell Biochem. 103, 1732–1746 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Shida, D. et al. Sphingosine 1-phosphate transactivates c-Met as well as epidermal growth factor receptor (EGFR) in human gastric cancer cells. FEBS Lett. 577, 333–338 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Sukocheva, O. et al. Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1. J. Cell Biol. 173, 301–310 (2006). This was the first example of so-called 'criss-cross' transactivation linking ER with SK1/S1P and EGFR transactivation in breast cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Martin, J. L., Lin, M. Z., McGowan, E. M. & Baxter, R. C. Potentiation of growth factor signalling by insulin-like growth factor-binding protein-3 in breast epithelial cells requires sphingosine kinase activity. J. Biol. Chem. 284, 25542–25552 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shida, D. et al. Lysophospholipids transactivate HER2/neu (erbB-2) in human gastric cancer cells. Biochem. Biophys. Res. Comm. 327, 907–914 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Maceyka, M., Alvarez, S. E., Milstien, S. & Spiegel, S. Filamin A links sphingosine kinase 1 and sphingosine-1-phosphate receptor 1 at lamellipodia to orchestrate cell migration. Mol. Cell. Biol. 28, 5687–5697 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hobson, J. P. et al. Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science 291, 1800–1803 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Rosenfeldt, H. M. et al. EDG-1 links the PDGF receptor to Src and focal adhesion kinase activation leading to lamellipodia formation and cell migration. FASEB J. 15, 2649–2659 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Baudhuin, L. M. et al. S1P3-mediated AKT activation and cross-talk with platelet-derived growth factor receptor (PDGFR). FASEB J. 18, 341–343 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Alderton, F. et al. Tethering of the platelet-derived growth factor beta receptor to G-protein coupled receptors: a novel platform for integrative signalling by these receptor classes in mammalian cells. J. Biol. Chem. 276, 28578–28585 (2001). This was the first demonstration of 'GPCR jacking involving a S1P 1 receptor and PDGFR regulating cell motility.

    Article  CAS  PubMed  Google Scholar 

  106. Waters, C. et al. Sphingosine 1-phosphate and platelet-derived growth factor (PDGF) act via PDGFβ receptor-sphingosine 1-phosphate receptor complexes in airway smooth muscle. J. Biol. Chem. 278, 6282–6290 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Waters, C. M. et al. Cell migration activated by platelet-derived growth factor receptor is blocked by an inverse agonist of the sphingosine 1-phosphate receptor-1. FASEB J. 20, 509–511 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Long, J. S., Natarajan, V., Tigyi, G., Pyne, S. & Pyne, N. J. The functional PDGFβ receptor-S1P1 receptor signalling complex is involved in regulating migration of mouse embryonic fibroblasts in response to platelet derived growth factor. Prostaglandins Other Lipid Mediat. 80, 1920–1929 (2006).

    Article  CAS  Google Scholar 

  109. Pyne, N. J. & Pyne, S. Sphingosine 1-phosphate, lysophosphatidic acid and growth factor signalling and termination. Biochim. Biophys. Acta 1781, 467–476 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Delcourt, N., Bockaert, J. & Marin, P. GPCR-jacking: from a new route in RTK signalling to a new concept in GPCR activation. Trends Pharmacol. Sci. 28, 602–607 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Chae, S. S., Paik, J. H., Furneaux, H. & Hla, T. Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. J Clin. Invest. 114, 1082–1089 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wu, W., Shu, X., Hovsepyan, H., Mosteller, R. D. & Broek, D. VEGF receptor expression and signalling in human bladder tumours. Oncogene 22, 3361–3370 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Taniguchi, K. et al. Sprouty4 deficiency potentiates Ras-independent angiogenic signals and tumour growth. Cancer Sci. 100, 1648–1654 (2009). This paper reports the first evidence for crosstalk regulation between VEGF, S1P and sprouty 4 and modulation of Ras-independent signalling and angiogenesis.

    Article  CAS  PubMed  Google Scholar 

  114. Shida, D. et al. Cross-talk between LPA1 and epidermal growth factor receptors mediates up-regulation of sphingosine kinase 1 to promote gastric cancer cell motility and invasion. Cancer Res. 68, 6569–6577 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sukocheva, O., Wang, L. Verrier, E., Vadas, M. A. & Xia, P. Restoring endocrine response in breast cancer cells by inhibition of the sphingosine kinase-1 signalling pathway. Endocrinology 150, 4484–4492 (2009). This was the first demonstration of role for SK1 in the induction of tamoxifen resistance.

    Article  CAS  PubMed  Google Scholar 

  116. Rayala, S. K. & Kumar, R. Sliding p21-activated kinase 1 to nucleus impacts Tamoxifen sensitivity. Biomed. Pharmacother. 61, 408–411 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Dayon, A. et al. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival PLoS ONE 4, e8408 (2009).

    Article  CAS  Google Scholar 

  118. Murillo, H., Huang, H. J., Schmidt, L. J., Smith, D. I. & Tindall, D. J. Role of PI3K signalling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology 142, 4795–4805 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Lin, H. K. et al. Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/AKT pathway in prostate cancer LNCaP cells with different passage numbers. J. Biol. Chem. 278, 50902–50907 (2003).

    Article  CAS  PubMed  Google Scholar 

  120. Ahmad, M., Long. J. S., Pyne, N. J. & Pyne. S. The effect of hypoxia on lipid phosphate receptor and sphingosine kinase expression and mitogen activated protein kinase signalling in human pulmonary smooth muscle cells. Prostaglandins Other Lipid Mediat. 79, 278–286 (2006). This was the first evidence to demonstrate the hypoxic-dependent regulation of SK1 and SK2 gene expression.

    Article  CAS  PubMed  Google Scholar 

  121. Schwalm, S. et al. Sphingosine kinase-1 is a hypoxia-regulated gene that stimulates migration of human endothelial cells. Biochim. Biophys. Res. Commun. 368, 1020–1025 (2008). This paper identifies two hypoxic responsive elements in the SK1 gene promoter.

    Article  CAS  Google Scholar 

  122. Anelli, V., Gault, C. R., Cheng, A. B. & Obeid, L. M. Sphingosine kinase is up-regulated during hypoxia in U87MG glioma cells. Role of hypoxia-inducible factors 1 and 2. J. Biol. Chem. 283, 3365–3375 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Ader, I., Brizuela, L., Bouquerel, P., Malavaud, B. & Cuvillier, O. Sphingosine kinase 1: a new modulator of hypoxia inducible factor 1alpha during hypoxia in human cancer cells. Cancer Res. 68, 8635–8642 (2008). This paper reports evidence for a role of SK1 in regulating HIF1α expression.

    Article  CAS  PubMed  Google Scholar 

  124. Schnitzer, S. E., Weigert, A., Zhou, J. & Brüne, B. Hypoxia enhances sphingosine kinase 2 activity and provokes sphingosine 1-phosphate-mediated chemoresistance in A549 lung cancer cells. Mol. Cancer Res. 7, 393–401 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Chen, N. & Karantza-Wadsworth, V. Role and regulation of autophagy in cancer. Biochim. Biophys. Acta 1793, 1516–1523 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lavieu, G. et al. Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation. J. Biol. Chem. 281, 8518–8527 (2006). This paper reports evidence of a role for SK1 in autophagic survival.

    Article  CAS  PubMed  Google Scholar 

  127. French, K. J. et al. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J. Pharmacol. Exp. Ther. 333, 129–139 (2010). This paper identified the first SK2-selective inhibitor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. French, K. J. et al. Antitumour activity of sphingosine kinase inhibitors. J. Pharmacol. Exp. Ther. 318, 596–603 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Beljanski, V., Knaak, C. & Smith, C. D. A novel sphingosine kinase inhibitor induces autophagy in tumour cells. J. Pharmacol. Exp. Ther. 333, 454–464 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chang, C. L. et al. S1P5 is required for sphingosine 1-phosphate-induced autophagy in human prostate PC-3 cells. Am. J. Physiol., Cell Physiol. 297, C451–C458 (2009).

    Article  CAS  Google Scholar 

  131. Oskouian, B. et al. Sphingosine 1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Proc. Natl Acad. Sci. USA 103, 17384–17389 (2006). This was the first demonstration that SPL is downregulated in colon cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nature Genet. 33, 49–54 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. Hibbs, K. et al. Differential gene expression in ovarian carcinoma: identification of potential biomarkers. Am. J. Pathol. 165, 397–314 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Bernardini, M. et al. High-resolution mapping of genomic imbalance and identification of gene expression profiles associated with differential chemotherapy response in serous epithelial ovarian cancer. Neoplasia 7, 603–613 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Min, J. et al. Sphingosine 1-phosphate lyase regulates sensitivity of human cells to select chemotherapy drugs in a p38-dependent manner. Mol. Cancer. Res. 3, 287–296 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Kawamori, T. et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J. 20, 386–388 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Johnson, K. R. et al. Role of human sphingosine-1-phosphate phosphatase 1 in the regulation of intra- and extracellular sphingosine-1-phosphate levels and cell viability. J. Biol. Chem. 278, 34541–34547 (2003).

    Article  CAS  PubMed  Google Scholar 

  138. Mechtcheriakova, D. et al. Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses. Cell. Signal. 19, 748–760 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Pettus, B. J. et al. The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-α. FASEB J. 17, 1411–1421 (2003). This paper reports evidence that S1P mediates the TNFα-induced production of inflammatory mediators.

    Article  CAS  PubMed  Google Scholar 

  140. Maines, L. W. et al. Suppression of ulcerative colitis in mice by orally available inhibitors of sphingosine kinase. Dig. Dis. Sci. 53, 997–1012 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Snider, A. J. et al. A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis. FASEB J. 23, 143–152 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. O'Brien, N. et al. Production and characterisation of monoclonal anti-sphingosine 1-phosphate antibodies. J. Lipid Res. 50, 2245–2257 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Endo. K., Igarashi, Y., Nisar, M., Zhou, Q. H. & Hakomori, S. Cell membrane signalling 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. 51, 1613–1618 (1991).

    CAS  PubMed  Google Scholar 

  144. Okoshi, H. et al. Cell membrane signalling as target in cancer therapy. II: inhibitory effect of N, N, N-trimethylsphingosine on metastatic potential of murine B16 melanoma cell line through blocking of tumor cell-dependent platelet aggregation. Cancer Res. 51, 6019–6024 (1991).

    CAS  PubMed  Google Scholar 

  145. Kedderis, L. B. et al. Toxicity of the protein kinase C inhibitor safingol administered alone and in combination with chemotherapeutic agents. Fundam. Appl. Toxicol. 25, 201–217 (1995).

    Article  CAS  PubMed  Google Scholar 

  146. Igarashi, Y. et al. Effect of chemically well-defined sphingosine and its N-methyl derivatives on protein kinase C and src kinase activities. Biochemistry 28, 6796–6800 (1989).

    Article  CAS  PubMed  Google Scholar 

  147. Sugiura, M. et al. Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization. J. Biol. Chem. 277, 23294–23300 (2002).

    Article  CAS  PubMed  Google Scholar 

  148. Megidish, T. et al. 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. 216, 739–747 (1995).

    Article  CAS  PubMed  Google Scholar 

  149. King, C. C. et al. Sphingosine is a novel activator of 3-phosphoinositide-dependent kinase 1. J. Biol. Chem. 275, 18108–18113 (2000).

    Article  CAS  PubMed  Google Scholar 

  150. McDonald, O. B., Hannun, Y. A., Reynolds, C. H. & Sahyoun, N. Activation of casein kinase II by sphingosine. J. Biol. Chem. 266, 21773–21776 (1991).

    Article  CAS  PubMed  Google Scholar 

  151. Schwartz, G. K. et al. A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. Clin. Cancer Res. 3, 537–543 (1997).

    CAS  PubMed  Google Scholar 

  152. Gamble, J. R. et al. Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects. Int. J. Cancer 118, 2412–2420 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. De Luca, T., Morré, D. M., Zhao, H. & Morré, D. J. NAD+/NADH and/or CoQ/CoQH2 ratios from plasma membrane electron transport may determine ceramide and sphingosine-1-phosphate levels accompanying G1 arrest and apoptosis. Biofactors 25, 43–60 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Paugh, S. W. et al. A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukaemia. Blood 112, 1382–1391 (2008). This paper identifiedthe first SK1-selective inhibitor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kapitonov, D. et al. Targeting sphingosine kinase 1 inhibits AKT signalling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res. 69, 6915–6923 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wong, L., Tan, S. S., Lam, Y. & Melendez, A. J. Synthesis and evaluation of sphingosine analogues as inhibitors of sphingosine kinases. J. Med. Chem. 52, 3618–3626 (2009).

    Article  CAS  PubMed  Google Scholar 

  157. Xiang, Y. et al. Discovery of novel sphingosine kinase 1 inhibitors. Bioorg. Med. Chem. Lett. 19, 6119–6121 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Kono, K., Tanaka, M., Ogita, T & Kohama, T. Characterisation of B-5354c, a new sphingosine kinase inhibitor, produced by a marine bacterium. J. Antibiot. (Tokyo) 53, 759–764 (2000).

    Article  CAS  Google Scholar 

  159. Kono. K., Tanaka, M., Ogita, T., Hosoya, T. & Koyama, T. F-12509A, a new sphingosine kinase inhibitor, produced by a discomycete. J. Antibiot. (Tokyo) 53, 12459–12466 (2000).

    Google Scholar 

  160. Kono, K. et al. S.-15183a and b, new sphingosine kinase inhibitors, produced by a fungus. J. Antibiot. (Tokyo) 54, 415–420 (2001).

    Article  CAS  Google Scholar 

  161. Huwiler, A. & Pfeilschifter, J. New players on the center stage: sphingosine 1-phosphate and its receptors as drug targets. Biochem. Pharmacol. 75, 1893–1900 (2008).

    Article  CAS  PubMed  Google Scholar 

  162. Sanchez, T. et al. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J. Biol. Chem. 278, 47281–47290 (2003).

    Article  CAS  PubMed  Google Scholar 

  163. Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphatereceptors. J. Biol. Chem. 277, 21453–21457 (2002).

    Article  CAS  PubMed  Google Scholar 

  164. Gräler, M. H. & Goetzl, E. J. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G protein-coupled receptors. FASEB J. 18, 551–553 (2004).

    Article  PubMed  CAS  Google Scholar 

  165. Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. van Meeteren, L. A., Brinkmann, V., Saulnier-Blache, J. S., Lynch, K. R. & Moolenaar, W. H. Anticancer activity of FTY720: phosphorylated FTY720 inhibits autotaxin, a metastasis-enhancing and angiogenic lysophospholipase D. Cancer Lett. 266, 203–208 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Payne, S. G. et al. The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood 109, 1077–1085 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bandhuvula, P., Tam, Y. Y., Oskouian, B. & Saba, J. D. The immune modulator FTY720 inhibits sphingosine 1-phosphate lyase activity. J. Biol. Chem. 280, 33697–33700 (2005).

    Article  CAS  PubMed  Google Scholar 

  169. Vessey, D. A. et al. Dimethylsphingosine and FTY720 inhibit the SK1 form but activate the SK2 form of sphingosine kinase from rat heart. J. Biochem. Mol. Toxicol. 21, 273–279 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Lahiri, S., Park, H., Laviad, E. L., Bittman, R. & Futerman, A. H. Ceramide synthesis is modulated by the sphingosine analogue FTY720 via a mixture of uncompetitive and noncompetitive inhibition of acyl-CoA chain length dependent manner. J. Biol. Chem. 284, 16090–16098 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Berdyshev, E. V. et al. FTY720 inhibits ceramide synthases and up-regulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. J. Biol. Chem. 284, 5467–5477 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Neviani, P. et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J. Clin. Invest. 117, 2408–2421 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Matsuoka, Y., Nagahara, Y., Ikekita, M. & Shinomiya, T. A novel immunosuppressive agent FTY720 induced AKT dephosphorylation in leukemia cells. Br. J. Pharmacol. 138, 1303–1312 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Azuma, H. et al. Selective cancer cell apoptosis induced by FTY720: evidence for a Bcl-dependent pathway and impairment in ERK activity. Anticancer Res. 23, 3183–3193 (2003).

    CAS  PubMed  Google Scholar 

  175. LaMontagne, K. et al. Antagonism of sphingosine 1-phosphate receptors by FTY720 inhibits angiogenesis and tumour vascularisation. Cancer Res. 66, 221–231 (2006). This paper demonstrates that FTY720 regresses tumour growth and promotes apoptosis through a mechanism involving the functional antagonism of S1P 1 in endothelial cells, thereby preventing neovascularization of the tumour.

    Article  CAS  PubMed  Google Scholar 

  176. Nagaoka, Y., Otsuki, K., Fujita, T. & Uesato, S. Effects of phosphorylation of immunomodulatory agent FTY720 (fingolimod) on antiproliferative activity against breast cancer and colon cancer cells. Biol. Pharm. Bull. 31, 1177–1181 (2008).

    Article  CAS  PubMed  Google Scholar 

  177. Schmid, G. et al. The immunosuppressant FTY720 inhibits tumor angiogenesis via the sphingosine 1-phosphate receptor 1. J. Cell. Biochem. 101, 259–270 (2007).

    Article  CAS  PubMed  Google Scholar 

  178. Chun, J. et al. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol. Rev. 54, 265–269 (2002).

    Article  CAS  PubMed  Google Scholar 

  179. Yoshida Y. et al. Sphingosine-1-phosphate receptor type 1 regulates glioma cell proliferation and correlates with patient survival. Int. J. Cancer. 126, 2341–2352 (2010).

    Article  CAS  PubMed  Google Scholar 

  180. Kothapalli R., Kusmartseva I. & Loughran TP. Characterization of a human sphingosine-1-phosphate receptor gene (S1P5) and its differential expression in LGL leukemia. Biochim. Biophys. Acta 1579, 117–123 (2002).

    Article  CAS  PubMed  Google Scholar 

  181. Kohama, T. et al. Molecular cloning and functional characterization of murine sphingosine kinase. J. Biol. Chem. 273, 23722–23728 (1998). This paper reports the first cloning of the SK1 isoform.

    Article  CAS  PubMed  Google Scholar 

  182. Liu, H. et al. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J. Biol. Chem. 275, 19513–19520 (2000). This paper reports the first cloning of the SK2 isoform.

    Article  CAS  PubMed  Google Scholar 

  183. Sweeney, E. A. et al. Sphingosine and its methylated derivative N, N-dimethylsphingosine (DMS) induce apoptosis in a variety of human cancer cell lines. Int. J. Cancer 66, 358–366 (1996).

    Article  CAS  PubMed  Google Scholar 

  184. Shirahama, T. et al. In vitro and in vivo induction of apoptosis by sphingosine and N, N-dimethylsphingosine in human epidermoid carcinoma KB-3-1 and its multidrug-resistant cells. Clin. Cancer Res. 3, 257–264 (1997).

    CAS  PubMed  Google Scholar 

  185. Cuvillier, O. & Levade, T. Sphingosine 1-phosphate antagonises apoptosis of human leukaemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria. Blood 98, 2828–2836 (2001).

    Article  CAS  PubMed  Google Scholar 

  186. Sachs, C. W., Safa, A. R., Harrison, S. D. & Fine, RL . Partial inhibition of multidrug resistance by safingol is independent of modulation of P-glycoprotein substrate activities and correlated with inhibition of protein kinase C. J. Biol. Chem. 270, 26639–26648 (1995).

    Article  CAS  PubMed  Google Scholar 

  187. Maines, L. W., Fitzpatrick, L. R., Green, C. L., Zhuang, Y. & Smith, C. D. Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn's disease Inflammopharmacology 18, 73–85 (2010).

    Article  CAS  PubMed  Google Scholar 

  188. Kono, K., Sugiura, M. & Kohama T . Inhibition of recombinant sphingosine kinases by novel inhibitors of microbial origin, F-12509A and B-5354c. J. Antibiot. (Tokyo) 55, 99–103 (2002).

    Article  CAS  Google Scholar 

  189. Bonhoure, E. et al. Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1. Leukemia 20, 95–102 (2006).

    Article  CAS  PubMed  Google Scholar 

  190. Mathews, T. P. et al. Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors. J. Med. Chem. 53, 2766–2778 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Davis, M. D., Clemens, J. J., Macdonald, T. L. & Lynch, K. R. Sphingosine 1-phosphate analogs as receptor antagonists. J. Biol. Chem. 280, 9833–9841 (2005).

    Article  CAS  PubMed  Google Scholar 

  192. Sanna, M. G. et al. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nature Chem. Biol. 2, 434–441 (2006).

    Article  CAS  Google Scholar 

  193. Wang, J. D. et al. Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation. Prostate 40, 50–55 (1999).

    Article  CAS  PubMed  Google Scholar 

  194. Ubai, T. et al. FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumour growth in mouse xenograft. Anticancer Res. 27, 75–88 (2007).

    CAS  PubMed  Google Scholar 

  195. Hung., J. H. et al. FTY720 induces apoptosis in hepatocellular carcinoma cells through activation of protein kinase C delta signalling. Cancer Res. 68, 1204–1212 (2008).

    Article  CAS  PubMed  Google Scholar 

  196. Azuma, H. et al. Induction of apoptosis in human bladder cancer cells in vitro and in vivo caused by FTY720 treatment. J. Urol. 169, 2372–2377 (2003).

    Article  CAS  PubMed  Google Scholar 

  197. Lee, T. K. et al. FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated AKT dephosphorylation. Carcinogenesis 25, 2397–2405 (2004).

    Article  CAS  PubMed  Google Scholar 

  198. Billich, A. et al. Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J. Biol. Chem. 278, 47408–47415 (2003).

    Article  CAS  PubMed  Google Scholar 

  199. Chua, C. W. et al. FTY720, a fungus metabolite, inhibits in vivo growth of androgen-independent prostate cancer. Int. J. Cancer. 117, 1039–1048 (2005).

    Article  CAS  PubMed  Google Scholar 

  200. Azuma, H. et al. Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models. Cancer Res. 62, 1410–1419 (2002).

    CAS  PubMed  Google Scholar 

  201. Ho, J. W. et al. Effects of a novel immunomodulating agent, FTY720, on tumor growth and angiogenesis in hepatocellular carcinoma. Mol. Cancer Ther. 4, 1430–1438 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all those that have worked in our research group past and present. The Pyne laboratory is supported by Cancer Research UK (23,158/A7536).

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Nigel J. Pyne's homepage

Susan Pyne's homepage

Glossary

Ceramide–sphingosine–S1P rheostat

The relative amounts of these three lipids, the balance of which can change to determine cell fate.

Non-oncogene addiction

The over-reliance of a cancer cell on a particular protein that is overexpressed but not mutated.

ABC transporters

A family of proteins that contribute to multi-drug resistance and transport lipids from the inner to the outer leaflet of the plasma membrane.

Translocation

The movement of a protein from one subcellular compartment to another.

Myristoylation and palmitoylation motif

A short sequence of amino acids that become modified by the addition of a lipid group, thereby enabling the membrane-anchoring of the protein.

Transactivation

The indirect activation of a specific receptor type, that is, its activation in the absence of stimulation by it own activator (agonist).

Integrative signalling

The cooperative signalling by two distinct receptor types and/or their downstream signalling components.

Autophagy

A normal cellular process in which cellular components are degraded through lysosomal mechanisms. It enables recycling and/or re-allocation of cellular components during cellular stress.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pyne, N., Pyne, S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer 10, 489–503 (2010). https://doi.org/10.1038/nrc2875

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2875

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer