Elsevier

Advances in Biological Regulation

Volume 60, January 2016, Pages 151-159
Advances in Biological Regulation

Review article
Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation

https://doi.org/10.1016/j.jbior.2015.09.001Get rights and content

Abstract

Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P1-5. In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P4) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis. Indeed, evidence will be presented here to demonstrate that S1P4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient T-ALL lymphoblasts and T-ALL cell lines, we have demonstrated that SK2 inhibitors promote T-ALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth arrest. In addition, the SK1 inhibitor, PF-543 exacerbates disease progression in an experimental autoimmune encephalomyelitis mouse model indicating that SK1 functions in an anti-inflammatory manner. Indeed, sphingosine, which accumulates upon inhibition of SK1 activity, and sphingosine-like compounds promote activation of the inflammasome, which is linked with multiple sclerosis, to stimulate formation of the pro-inflammatory mediator, IL-1β. Such compounds could be exploited to produce antagonists that diminish exaggerated inflammation in disease. The therapeutic potential of modifying the SK-S1P receptor pathway in cancer and inflammation will therefore, be reviewed.

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

References (62)

  • J.S. Long et al.

    Sphingosine 1-phosphate receptor 4 uses HER2 (ERBB2) to regulate extracellular signal regulated kinase-1/2 in MDA-MB-453 breast cancer cells

    J. Biol. Chem.

    (2010)
  • C. Loveridge et al.

    The sphingosine kinase 1 inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells

    J. Biol. Chem.

    (2010)
  • K. Nakahara et al.

    The Sjögren–Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway

    Mol. Cell.

    (2012)
  • M. Nagahashi et al.

    Sphingosine-1-phosphate in chronic intestinal inflammation and cancer

    Adv. Biol. Regul.

    (2014)
  • J. Newton et al.

    Revisiting the sphingolipid rheostat: evolving concepts in cancer therapy

    Exp. Cell Res.

    (2015)
  • J. Ohotski et al.

    Sphingosine kinase 2 prevents the nuclear translocation of sphingosine 1-phosphate receptor-2 and tyrosine 416 phosphorylated c-Src and increases estrogen receptor negative MDA-MB-231 breast cancer cell growth: the role of sphingosine 1- phosphate receptor-4

    Cell. Signal

    (2014)
  • S. Pyne et al.

    Role of sphingosine kinases and lipid phosphate phosphatases in regulating spatial sphingosine 1-phosphate signalling in health and disease

    Cell. Signal

    (2009)
  • N.J. Pyne et al.

    The role of sphingosine 1-phosphate in inflammation and cancer

    Adv. Biol. Regul.

    (2014)
  • N.J. Pyne et al.

    Sphingosine 1-phosphate is a missing link between chronic inflammation and colon cancer

    Cancer Cell.

    (2013)
  • D. Siow et al.

    Regulation of de novo sphingolipid biosynthesis by the ORMDL proteins and sphingosine kinase-1

    Adv. Biol. Regul.

    (2015)
  • F. Tonelli et al.

    FTY720 and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 and promote its proteasomal degradation in human pulmonary artery smooth muscle breast cancer and androgen-independent prostate cancer cells

    Cell. Signal

    (2010)
  • M. Vadas et al.

    The role of sphingosine kinase 1 in cancer: oncogene or non-oncogene addiction?

    Biochim. Biophys. Acta

    (2008)
  • C. Watson et al.

    High expression of sphingosine 1-phosphate receptors, S1P1 and S1P3, sphingosine kinase 1, and extracellular signal-regulated kinase-1/2 is associated with development of tamoxifen resistance in estrogen receptor-positive breast cancer patients

    Am. J. Pathol.

    (2010)
  • D.G. Watson et al.

    The roles of sphingosine kinases 1 and 2 in regulating the Warburg effect in prostate cancer cells

    Cell. Signal

    (2013)
  • P. Xia et al.

    An oncogenic role of sphingosine kinase

    Curr. Biol.

    (2000)
  • H. Zhou et al.

    Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis

    J. Biol. Chem.

    (1998)
  • V. Albinet et al.

    Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells

    Oncogene

    (2014)
  • D.J. Baek et al.

    Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors

    J. Med. Chem.

    (2013)
  • S.D. Boomkamp et al.

    Effect of ether glycerol lipids on interleukin-1β release and experimental autoimmune encephalomyelitis

    Chem. Phys. Lipids

    (2015)
  • D. Brough et al.

    Caspase-1-dependent processing of prointerleukin-1 beta is cytosolic and precedes cell death

    J. Cell Sci.

    (2007)
  • H.S. Byun et al.

    Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells

    MedChemComm

    (2013)
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