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Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond

Nature Reviews Drug Discovery volume 12, pages 688–702 (2013)Cite this article

Subjects

Key Points

  • Sphingosine-1-phosphate (S1P) is a bioactive signalling molecule that is involved in several pathways that are crucial for health, and it has been implicated in disorders including cancer and inflammatory diseases. Efforts are underway to pharmacologically regulate S1P synthesis, degradation, export and receptor activation.

  • S1P is generated by two intracellular kinases — sphingosine kinase 1 (SPHK1) and SPHK2 — that are conserved from yeast to humans. SPHK1 typically promotes cell growth and inhibits apoptosis, and its upregulation has been linked to several types of cancer.

  • Intracellular S1P can be exported outside cells by several ATP-binding cassette (ABC) transporters and the major facilitator superfamily member SPNS2, which regulates S1P secretion from endothelial and lymphendothelial cells and is an attractive new therapeutic target. Many receptor agonists and stimuli induce the synthesis and export of S1P.

  • Extracellular S1P can bind to a family of five G protein-coupled receptors (S1P receptor 1 (S1PR1) to S1PR5) that can be coupled to multiple Gα proteins, thus leading to multiple cellular effects. These receptors are the targets of various compounds that are in different stages of drug development. In addition, S1PR1 is a target of fingolimod, which is used clinically for the treatment of multiple sclerosis.

  • S1PRs control the movement of cells into and out of the blood, circulating lymph and other tissues. Fingolimod and other compounds that target S1PR1 are being used to disrupt lymphocyte egress from lymph nodes in relapsing and remitting multiple sclerosis. Clinical trials are underway to investigate the efficacy of these drugs in other autoimmune diseases, including rheumatoid arthritis and lupus.

  • Other S1PRs are not as well studied, but they all have potential pathophysiological roles. S1PR2 typically inhibits the migration of osteoclasts and promotes osteoclast retention in bone and thus bone resorption. S1PR3 promotes cancer growth and vascular leakage during sepsis. S1PR4 has been implicated in certain immune cell functions, including dendritic cell function and T helper 17 (TH17) cell differentiation. Similar to the role of S1PR1 in lymphocyte trafficking, S1PR5 is required for the trafficking of natural killer cells into peripheral tissues.

Abstract

The bioactive lipid sphingosine-1-phosphate (S1P) is involved in multiple cellular signalling systems and has a pivotal role in the control of immune cell trafficking. As such, S1P has been implicated in disorders such as cancer and inflammatory diseases. This Review discusses the ways in which S1P might be therapeutically targeted — for example, via the development of chemical inhibitors that target the generation, transport and degradation of S1P and via the development of specific S1P receptor agonists. We also highlight recent conflicting results observed in preclinical studies targeting S1P and discuss ongoing clinical trials in this field.

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Figure 1: S1P biosynthesis, degradation, export and signalling.
Figure 2: The balance between beneficial and detrimental effects of S1PR1 agonists and antagonists.
Figure 3: The S1PR1–STAT3 axis linking inflammation and cancer.
Figure 4: S1PR1-mediated suppression of sprouting angiogenesis and stabilization of blood vessels.

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Acknowledgements

Work in the laboratory of S.S. is supported by grants R37GM043880 and RO1CA61774 from the US National Institutes of Health (NIH). The work of G.T.K. is supported by the NIH grant T32 HL094290.

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Author notes

  1. Gregory T. Kunkel and Michael Maceyka: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University School of Medicine, 1101 E. Marshall Street, 2-017 Sanger Hall, Richmond, 23298, Virginia, USA

    Gregory T. Kunkel, Michael Maceyka, Sheldon Milstien & Sarah Spiegel

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  1. Gregory T. Kunkel
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Correspondence to Sarah Spiegel.

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Glossary

Angiogenesis

The development of new blood vessels. Angiogenesis is required in development and tissue repair, as well as pathologically for tumour progression.

Fingolimod

A sphingosine-1-phosphate receptor (S1PR) agonist. However, sustained activation of S1PR1 by fingolimod leads to degradation of S1PR1. Thus, fingolimod is often referred to as a 'functional antagonist' of S1PR1, particularly in its role in lymphocyte trafficking.

Histone deacetylases

(HDACs). Proteins that remove acetyl groups from specific histone lysine residues, thus altering gene transcription.

ABC transporters

(ATP-binding cassette transporters). A family of proteins that transport small molecules across the membrane, including drugs and lipids. Several of these proteins have been shown to transport sphingosine-1-phosphate.

'Inside-out' signalling

A model whereby agonists such as growth factors promote the production of sphingosine-1-phosphate (S1P) within the cell. This S1P is then exported outside the cell to signal through cell surface S1P receptors in an autocrine and/or paracrine manner.

Lymphopenia

An abnormally low level of lymphocytes in the blood.

Sphingolipid rheostat concept

A concept that describes how the metabolic balance between sphingosine-1-phosphate (S1P) and ceramide regulates cell fate. S1P-mediated signals mostly regulate cell survival and proliferation, whereas ceramide-mediated signals regulate growth inhibition and apoptosis.

Myeloid cell

A blood cell type that includes macrophages, monocytes, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes and dendritic cells but not lymphocytes.

Lymphangiogenesis

The development of new lymph vessels. Lymphangiogenesis is required in development and for tissue repair, as well as for the metastasis of some tumours, such as breast cancer tumours.

Sjögren–Larsson syndrome

An autosomal recessive form of ichthyosis (scaly, dry, thickened skin) that is characterized by spastic paraplegia and mild to moderate intellectual disability.

Ichthyosis

A family of mostly genetic skin disorders characterized by dry, thickened, scaly skin, often with cracks.

mdx mice

A mouse model of Duchenne muscular dystrophy, which is a muscle-wasting disease that is caused by a mutation in the X-linked dystrophin gene, leading to loss of expression of the dystrophin protein.

Plaque psoriasis

An autoimmune disorder of the skin in which the patient typically presents with scaly patches of skin with a red and/or white hue.

Bradycardia

A decreased resting heart rate that results in in dizziness, weakness and fatigue.

Macular oedema

The accumulation of fluid and protein in the macula (visual field), leading to swelling and loss of vision.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of inflammation-induced demyelinating disease, often used as a proxy for human multiple sclerosis.

Cytokine storm

A potentially fatal immune reaction consisting of a positive feedback loop between highly elevated levels of many cytokines with immune cells.

Sprouting angiogenesis

The process of developing new blood vessels in which angiogenic factors bind to receptors on endothelial cells of a blood vessel. These cells grow out and form sprouts connecting to other blood vessels.

Laminar shear stress

The stress on tissues derived from the flow of a fluid through the vessel.

Osteoporosis

A bone-thinning disease that is characterized by overactive bone resorption by osteoclasts, reduced bone formation by osteoblasts, or both.

Sepsis syndrome

A life-threatening systemic response to severe infection that is characterized by vascular leakage and oedema, hypo- or hyperthermia, low blood pressure and reduced lung function.

Dendritic cell

A cell type that has a central role in the adaptive immune response by presenting antigens to lymphocytes and causing their activation.

TH17 cell

T helper 17 cell; a subset of T helper cells that secrete pro-inflammatory cytokines.

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Kunkel, G., Maceyka, M., Milstien, S. et al. Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov 12, 688–702 (2013). https://doi.org/10.1038/nrd4099

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