Review articleRole of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation
Introduction
Formation of the bioactive lipid, sphingosine 1-phosphate (S1P) is catalysed by sphingosine kinase. There are two isoforms of sphingosine kinase (SK1 and SK2) which differ in their subcellular localisations, regulation and functions (Pyne et al., 2009). The S1P formed by these enzymes can either be exported from cells (through transporter proteins e.g. Spns2) and act as a ligand on a family of five S1P-specific G protein coupled receptors (S1P1–5) (Blaho and Hla, 2014) or can bind to specific intracellular target proteins. For instance S1P formed by nuclear SK2 inhibits HDAC1/2 activity to induce c-fos and p21 expression (Hait et al., 2009). Dephosphorylation of S1P is catalysed by S1P phosphatase and the sphingosine formed is then acylated to ceramide catalysed by ceramide synthase isoforms (Stiban et al., 2010). S1P can also be irreversibly cleaved by S1P lyase to produce (E)-2 hexadecenal and phosphoethanolamine (Degagné and Saba, 2014). The interconversion of ceramide to sphingosine and S1P has been termed the sphingolipid rheostat. In this model, shifting the balance toward ceramide induces apoptosis, while increased S1P formation promotes cell survival (Newton et al., 2015). For instance, ceramide activates protein phosphatase 2A (Dobrowsky et al., 1993), which dephosphorylates phosphorylated AKT (Zhou et al., 1998) and thereby alters BAD/Bcl2 regulation to induce apoptosis (Zundel and Giaccia, 1998). In contrast, S1P promotes cell survival, involving for instance, activation of the extracellular signal regulated kinase-1/2 (ERK-1/2) pathway (Pyne et al., 2009). However, the sphingolipid rheostat exhibits greater complexity, as certain ceramide species regulate processes other than apoptosis, such as autophagy and proliferation. This suggests temporal and spatial regulation, where the functionality of the sphingolipid rheostat is governed by compartmentalised signalling involving, for instance, ceramide synthase isoforms that produce different ceramide species with specific stress-dependent signalling functions that govern a defined cellular outcome e.g. apoptosis versus proliferation. The conversion of S1P to (E)-2 hexadecenal and phosphoethanolamine is also considered an exit point in the sphingolipid metabolic pathway, but (E)-2 hexadecenal has potential signalling functions (Kumar et al., 2011) and both (E)-2 hexadecenal and phosphoethanolamine can be further metabolised to produce phospholipids that have additional defined signalling functions in cells (Nakahara et al., 2012). Therefore, the regulation of the sphingolipid rheostat in different cellular compartments is likely to impact significantly on lipid signalling pathways that regulate cell context specific physiology and pathophysiology.
Section snippets
S1P receptors, sphingosine kinase and cancer
S1P has been implicated in regulating cellular processes, some of which underlie the hallmarks of cancer. First, over-expression of SK1 promotes the Ras dependent transformation of fibroblasts into fibrosarcoma (Xia et al., 2000). Second, S1P promotes neovascularisation of tumours (LaMontagne et al., 2006). Third, SK1 maintains the survival of cancer cells (a process termed ‘non-oncogenic’ addiction (Vadas et al., 2008)), promotes acquisition of replicative immortality and drives
SK2 and T-ALL
Acute lymphoblastic leukaemia is the most common type of paediatric cancer, affecting approximately one in every 2000 children, mostly at between 2 and 5 years of age. Despite aggressive treatment approaches, including transplantation and new salvage regimens, most children with relapsed T-cell acute lymphoblastic leukaemia (T-ALL) will not be cured. In contrast, the clinical prognosis for adults with T-ALL, which is more common, is very poor indeed, with cure rates of, at best, 40%. T-ALL
Ubiquitin-proteasomal degradation of SK1
We have synthesised and characterised a number of structurally similar SK1 selective orthosteric inhibitors, including RB-005 (1-(4-octylphenethyl)piperidin-4-ol) (Baek et al., 2013) and 55-21 (1-deoxysphinganine analogue) (Byun et al., 2013) and allosteric SK1 inhibitors, such as (S)-FTY7200 vinylphosphonate (Lim et al., 2011b). A common feature of these inhibitors is that they induce the ubiquitin-proteasomal degradation of SK1 in solid cancer cell lines (Loveridge et al., 2010, Tonelli
Sphingosine kinase 1, sphingosine and the inflammasome
Multiple sclerosis is an autoimmune inflammatory demyelinating disease that involves destructive effects of reactive T-lymphocytes. A prognostic relationship exists between IL-1β levels, disease progression and mutation of the NOD-like receptor family, pyrin domain containing 3 (Nlrp3) gene, and which is associated with multiple sclerosis-like lesions (Compeyrot-Lacassagne et al., 2009, Dodé et al., 2002). This is supported by evidence showing that NLRP3 (Nlrp3−/−) mice develop milder symptoms
Conclusion
The therapeutic potential of targeting the S1P signalling pathway in cancer and inflammation provides significant promise. This extends to targeting S1P receptor systems and the enzymes involved in promoting formation/degradation of S1P. Compounds can be designed to force ‘mild’ or ‘severe’ phenotypes based on whether they conformationally induce proteasomal degradation of SK1 or cause activation of the proteasome to instigate catastrophic collapse of cancer signalling networks. In terms of
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