Sphingosine 1-phosphate and cancer View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-06-17

AUTHORS

Nigel J. Pyne, Susan Pyne

ABSTRACT

Key PointsSphingosine 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. More... »

PAGES

489-503

References to SciGraph publications

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    URI

    http://scigraph.springernature.com/pub.10.1038/nrc2875

    DOI

    http://dx.doi.org/10.1038/nrc2875

    DIMENSIONS

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    33 schema:description Key PointsSphingosine 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.
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