Recent advances in the role of Sphingosine 1-phosphate in cancer

Pyne, Nigel J. and Pyne, Susan (2020) Recent advances in the role of Sphingosine 1-phosphate in cancer. FEBS Letters, 594 (22). pp. 3583-3601. ISSN 0014-5793 (

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Sphingosine 1-phosphate (S1P) is a bioactive lipid that binds to a family of G protein-coupled receptors (S1P 1–5) and intracellular targets, such as HDAC1/2, that are functional in normal and pathophysiologic cell biology. There is a significant role for sphingosine 1-phosphate in cancer underpinning the so-called hallmarks, such as transformation and replicative immortality. In this review, we survey the most recent developments concerning the role of sphingosine 1-phosphate receptors, sphingosine kinase and S1P lyase in cancer and the prognostic indications of these receptors and enzymes in terms of disease-specific survival and recurrence. We also provide evidence for identification of new therapeutic approaches targeting sphingosine 1-phosphate to prevent neovascularisation, to revert aggressive and drug-resistant cancers to more amenable forms sensitive to chemotherapy, and to induce cytotoxicity in cancer cells. Finally, we briefly describe current advances in the development of isoform-specific inhibitors of sphingosine kinases for potential use in the treatment of various cancers, where these enzymes have a predominant role. This review will therefore highlight sphingosine 1-phosphate signalling as a promising translational target for precision medicine in stratified cancer patients.