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

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.

Figure 1. S1P biosynthesis, degradation, export and signalling

Sphingosine, the substrate of sphingosine kinases (SPHKs), is not generated de novo but through the degradation of complex sphingolipids and ceramide, which can occur in the lysosome as well as on the endoplasmic reticulum (ER) and other membranes. SPHK1 is mainly located in the cytosol and is translocated to the plasma membrane upon activation. This leads to the formation of sphingosine-1-phosphate (S1P), which can be exported out of the cell by specific transporters. Binding to S1P receptors (S1PRs) initiates downstream signalling pathways. SPHK2 is localized to the ER, mitochondria and nucleus. At the ER, S1P is irreversibly degraded by S1P lyase or dephosphorylated by S1P phosphatases to sphingosine, which is reused for the synthesis of ceramide. S1P produced in the mitochondria and nucleus by SPHK2 also has direct intracellular targets. These include prohibitin 2 (PHB2), which stabilizes cytochrome c oxidase (COX), and histone deacetylases (HDACs), which remove acetyl groups from histones. ABC, ATP-binding cassette; PalCoA, palmitoyl-CoA; PE, phosphoethanolamine; SGPP1, S1P phosphatase 1; SGPP2, S1P phosphatase 2.

Figure 2. The balance between beneficial and detrimental effects of S1PR1 agonists and antagonists

Agonists and antagonists of sphingosine-1-phosphate receptor 1 (S1PR1) can induce both lymphopenia and the bradycardic side effects. Fingolimod acts as both an agonist and functional antagonist of S1PR1.

Figure 3. The S1PR1–STAT3 axis linking inflammation and cancer

Sphingosine kinase 1 (SPHK1) is upregulated in tumour cells to produce sphingosine-1-phosphate (S1P); this activates S1P receptor 1 (S1PR1), which leads to the activation of signal transducer and activator of transcription 3 (STAT3). Reciprocally, STAT3 enhances the transcription of its target genes, including S1PR1. S1P is also involved in the activation of nuclear factor-κB (NF-κB), which regulates the transcription of the pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin-6 (IL-6). TNF stimulates SPHK1 to further maintain NF-κB activation, and IL-6 induces STAT3 activation. In addition to upregulating SPHK1 in tumour cells, inflammation upregulates SPHK1 in inflammatory and/or myeloid cells in a manner similar to that in tumour cells. Communication among tumour cells, the host microenvironment and inflammatory cells via systemic S1P regulates metastasis. Targeting SPHK1 and S1PR1 — for example, with fingolimod — interferes with these amplification cascades and cancer progression. IL-6R, IL-6 receptor; TNFR, TNF receptor; TRAF2, TNF receptor-associated factor 2.

Figure 4. S1PR1-mediated suppression of sprouting angiogenesis and stabilization of blood vessels

a | Sphingosine-1-phosphate receptor 1 (S1PR1) is expressed in vascular endothelial cells and colocalizes with vascular endothelial cadherin in regions of normal blood flow, but is internalized in regions with turbulent blood flow (not shown). b | Engagement of vascular endothelial growth factor (VEGF) signalling in the growing vascular front induces the formation of sprouts consisting of tip cells that extend out from the blood vessel and stalk cells. The sprouting vascular front, the tip and stalk cell region express very low levels of S1PR1 (REF. 88); alternatively, S1PR1 is expressed on tip cells but they are not exposed to S1P present in the bloodstream. c | After its fusion into a primary vascular loop, which is a key step in the initiation of blood flow, S1P activates S1PR1. Activation of S1PR1 enhances the formation of adherens junctions, inhibits VEGF signalling, suppresses sprouting and stabilizes new vascular connections. VEGFR, VEGF receptor.