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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.

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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.

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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).

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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.

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

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