There is an increasing body of evidence demonstrating a critical role for the bioactive lipid S1P (sphingosine 1-phosphate) in cancer. S1P is synthesized and metabolized by a number of enzymes, including sphingosine kinase, S1P lyase and S1P phosphatases. S1P binds to cell-surface G-protein-coupled receptors (S1P1–S1P5) to elicit cell responses and can also regulate, by direct binding, a number of intracellular targets such as HDAC (histone deacetylase) 1/2 to induce epigenetic regulation. S1P is involved in cancer progression including cell transformation/oncogenesis, cell survival/apoptosis, cell migration/metastasis and tumour microenvironment neovascularization. In the present paper, we describe our research findings regarding the correlation of sphingosine kinase 1 and S1P receptor expression in tumours with clinical outcome and we define some of the molecular mechanisms underlying the involvement of sphingosine kinase 1 and S1P receptors in the formation of a cancer cell migratory phenotype. The role of sphingosine kinase 1 in the acquisition of chemotherapeutic resistance and the interaction of S1P receptors with oncogenes such as HER2 is also reviewed. We also discuss novel aspects of the use of small-molecule inhibitors of sphingosine kinase 1 in terms of allosterism, ubiquitin–proteasomal degradation of sphingosine kinase 1 and anticancer activity. Finally, we describe how S1P receptor-modulating agents abrogate S1P receptor–receptor tyrosine kinase interactions, with potential to inhibit growth-factor-dependent cancer progression.
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February 2012
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Conference Article|
January 19 2012
Sphingosine 1-phosphate signalling in cancer
Nigel J. Pyne;
Nigel J. Pyne
1
*Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, U.K.
1To whom correspondence should be addressed (email n.j.pyne@strath.ac.uk).
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Francesca Tonelli;
Francesca Tonelli
*Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, U.K.
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Keng Gat Lim;
Keng Gat Lim
*Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, U.K.
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Jaclyn S. Long;
Jaclyn S. Long
*Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, U.K.
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Joanne Edwards;
Joanne Edwards
†Section of Surgery, Division of Cancer Studies and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow G11 6NT, U.K.
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Susan Pyne
Susan Pyne
*Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, U.K.
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Publisher: Portland Press Ltd
Received:
May 09 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (1): 94–100.
Article history
Received:
May 09 2011
Citation
Nigel J. Pyne, Francesca Tonelli, Keng Gat Lim, Jaclyn S. Long, Joanne Edwards, Susan Pyne; Sphingosine 1-phosphate signalling in cancer. Biochem Soc Trans 1 February 2012; 40 (1): 94–100. doi: https://doi.org/10.1042/BST20110602
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