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Sphingosine 1-phosphate (S1P) is a membrane-derived lysophospholipid that acts primarily as an extracellular signaling molecule. Signals initiated by S1P are transduced by five G protein-coupled receptors, named S1P1–5. Cellular and temporal expression of the S1P receptors (S1PRs) determine their specific roles in various organ systems, but they are particularly critical for regulation of the cardiovascular, immune, and nervous systems, with the most well-known contributions of S1PR signaling being modulation of vascular barrier function, vascular tone, and regulation of lymphocyte trafficking. However, our knowledge of S1PR biology is rapidly increasing as they become attractive therapeutic targets in several diseases, such as chronic inflammatory pathologies, autoimmunity, and cancer. Understanding how the S1PRs regulate interactions between biological systems will allow for greater efficacy in this novel therapeutic strategy as well as characterization of complex physiological networks. Because of the rapidly expanding body of research, this review will focus on the most recent advances in S1PRs.
Sphingosine 1-phosphate [2S-amino-1-(dihydrogen phosphate)-4E-octadecene-1,3R-diol] (S1P) is a simple membrane-derived lysophospholipid with regulatory roles in almost all facets of mammalian biology (
). Concentrations of S1P in blood and lymph plasmas are high, in the high nanomolar to low micromolar ranges, whereas S1P concentrations in tissues are kept low, creating an S1P gradient (
). Expression patterns of the five S1P receptors (S1PRs) vary in tissues and also during development and ageing. S1P1, S1P2, and S1P3 are essentially ubiquitously expressed, whereas expression of S1P4 and S1P5 are highly restricted to distinct cell types (
Production of S1P can be initiated by external or internal signals, which lead to activation of the biosynthetic pathway beginning with metabolism of membrane SM to ceramide by SMases (
Sphingosine 1-phosphate is a blood constituent released from activated platelets, possibly playing a variety of physiological and pathophysiological roles.
Fig. 1Synthesis and export of S1P. S1P synthesis primarily begins with metabolism of membrane SM. Once synthesized, S1P can be irreversibly degraded to phosphoethanolamine and hexadecenal by S1P lyase, or actively transported out of the cell. Once outside of the cell, S1P is found bound to ApoM or albumin. Spns2, spinster 2.
Although there are proposed intracellular roles for S1P, it is often transported out of the cell where it can act in an autocrine or paracrine manner on S1PRs (
). Transport out of the cell may occur via several transporters; however, the only bona fide transporter to date is spinster 2, which is also capable of FTY720 (fingolimod/Gilenya; Novartis) export (
). How albumin or ApoM deliver S1P to specific S1PRs has yet to be characterized.
AGONISTS AND ANTAGONISTS
There are several well-characterized agonists and antagonists of S1PRs; however, most compounds have been directed toward modulating the activity of S1P1. FTY720 is the prototypical S1PR agonist and was approved by the US Food and Drug Administration as a first line oral therapy for relapsing-remitting multiple sclerosis (MS) (
). Although FTY720 acts as an agonist at picomolar to nanomolar concentrations on S1P1 and S1P3–5, it also acts as a functional antagonist for S1P1 by inducing receptor endocytosis and degradation of this receptor (
). This promiscuity may be responsible for adverse affects, such as acute bradycardia (decreased heart rate) and hypertension, seen in fingolimod-treated patients (
). Initial results from rodent studies indicated that FTY720 phosphate activation of S1P3 was responsible for both bradycardia and hypertension; however, treatment of humans with more selective agonists indicated that S1P1 agonism was responsible for reduced heart rate, whereas S1P3 signaling contributed to the development of hypertension (
Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: results from a 12-week, open-label pilot study in multiple sclerosis patients.
). The divergent utilization of S1P1 and S1P3 in rodents versus primates for the regulation of these coordinated physiological functions highlights the difficulties encountered upon extrapolation from rodent model-based characterization of S1PR function to human disease therapies.
SEW2871 is an S1P1-specific agonist that activates ERK1/2, AKT, and Rac signals at nanomolar concentrations and induces receptor internalization and recycling; however, it has a relatively short half-life in vivo (
). The only known compound with activity at S1P2 is JTE-013, an antagonist with an IC50 of approximately 20 nM, which blocks S1P2 signaling through Rho-associated protein kinase (ROCK) and phosphatase and tensin homologue (
). The S1P2 specificity of JTE-013 has been called into question by several studies that indicate it may have activity at S1P4 as well as non-S1PR-mediated effects (
Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor-null mice and pharmacological tools.
Many effects of S1P on the vasculature are due to expression of S1P1 by the endothelium. S1P1, originally named EDG1 (endothelial differentiation gene), was discovered during a search for immediate early genes regulating endothelial cell differentiation (
An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors.
). Although S1pr1−/− embryos developed a vascular network, they died in utero at E12.5– E14.5 due to defective coverage of large vessels by pericytes and vascular smooth muscle cells (VSMCs) (
). Specifically, the aorta exhibited severe morphological abnormalities, endothelial hypersprouting, and altered VSMC recruitment and localization (Fig. 2) (
). The generation of inducible cell-specific S1P1 knockout mice has clarified the roles of endothelial cells (ECs) or VSMC S1P1 in the regulation of postnatal vascular development, maturation, and function. In the developing retinal vasculature, S1P1 expression is restricted to the ECs and increases with vessel maturity, as the lowest levels of expression are found at the vascular leading front (
). Postnatal deletion of EC S1pr1 did not affect mural cell recruitment or vessel coverage in the retina; however, angiogenic hypersprouting occurred, characterized by dilated vessels and increases in the number of branch points and tip cells. Induced over-expression of EC S1P1 suppressed vascular sprouting (
). Changes in the vascular architecture of EC S1pr1−/− mice were accompanied by increased vascular permeability, resulting from altered vascular endothelial cadherin localization at endothelial cell-cell junctions (
). These data confirmed numerous earlier in vitro studies describing the necessity of EC S1P1 for the maintenance of vascular barrier function through adherens junction formation induced by activation of Rac after Gαi coupling to S1P1 (Fig. 2) (
Fig. 2Expression of S1PRs and responses by endothelial cells. Endothelial cells express S1P1, S1P2, and S1P3 protein. Endothelial cells may express different S1PRs depending on activation status.
Maintenance and formation of adherens junctions was dependent on S1P1 signaling initiated not only by ligand, but also by fluid shear stress (Fig. 2). Examination of murine aortae found that areas of turbulent flow (the lesser curvature) had poor endothelial cell alignment and S1P1 relocalized from the EC surface to endocytic vesicles, whereas in the descending aorta, an area of laminar flow, S1P1 and vascular endothelial cadherin colocalized to the cell surface (
). Additionally, maintenance of vascular homeostasis by the endothelial glycocalyx, which is also susceptible to changes in flow dynamics, was dependent upon S1P1-induced inhibition of matrix metalloproteinase (
Mice with endothelium-specific deletion of S1P1 developed severe pathology in a model of renal ischemia/reperfusion injury, both in the kidneys and the liver, characterized by elevated plasma creatinine, alanine transferase, and tissue necrosis (
). Conversely, of the five S1PRs, S1P2 mRNA in the kidney was most increased upon renal ischemia/reperfusion, and mice deficient in S1P2 developed significantly less pathology compared with WT controls (
). When S1pr2−/− mice were treated with the S1P1 antagonist, W146, before ischemia/reperfusion, they were no longer protected from renal injury, suggesting that S1P1 and S1P2 in the renal vasculare endothelium play protective and injurious roles, respectively, in kidney injury and disease (
The pro-inflammatory tendency of S1P2 is supported by in vitro studies suggesting a paracrine feedback loop involving EC TNFα induction of S1P2 expression leading to activation of nuclear factor (NF)-κB and increases in intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (
). In vivo studies utilizing S1pr2−/− mice and a model of acute inflammation, endotoxemia, further support the conclusion that S1P2 is an important regulator of vascular activation and therefore, permeability (
). Induction of endotoxemia in mice lacking S1pr2 in the stroma and not in the bone marrow (BM) compartment resulted in decreased vascular permeability, VCAM-1 and ICAM-1 expression, and more rapid resolution (
). These recent studies reaffirm the conclusion that an antagonistic relationship exists between S1P1 and S1P2 in the vascular endothelium during tissue injury and disease.
Lymphatic endothelium also expresses S1PRs, although more interest has focused on the role it may play in S1P metabolism (
). Examination of murine iliac collecting lymph vessels demonstrated that while S1P does not induce nitric oxide or prostaglandin release, signaling via S1P2 regulates tonic contractility of lymph vessels, as shown using S1P2 inhibition by JTE013 (
S1PRs regulate many aspects of immune cell biology. The best known is the regulation by S1P1 of lymphocyte migration out of the secondary lymphoid organs into the blood and lymph (Fig. 3) (
). However, this is not the only role for S1P1 in lymphocytes, and roles for the other four S1PRs in the immune system have recently been revealed.
Fig. 3Expression of S1PRs and responses by cells of the acquired immune system. T cells express S1P1 and S1P4, B cells express S1P1, S1P2, S1P3, and S1P4, and NK cells express S1P1 and S1P5. Cells do not necessarily express all of the illustrated S1PRs at one time, but may have differential expression during different stages of maturation or activation.
The contribution of S1PRs to regulation of the immune response has been studied extensively in the context of experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS (
). Although EAE and MS are considered to be primarily diseases of the immune system, the role of S1PRs on neural cells is also gaining an appreciation and will be discussed later. FTY720 is a Sph analog that is phosphorylated, acts on S1P1,3–5, and was the first US Food and Drug Administration approved oral therapy for MS (
). However, T cell S1P1 may also regulate the activation and differentiation status of these immune cells. Deletion of T cell S1P1 significantly suppresses the ability of these cells to be polarized to T-helper (Th)17 in vitro (
). Conversely, when EAE was induced in mice expressing an internalization-defective S1P1 (S5A), this significantly increased polarization of T cells to the Th17 phenotype resulting in increased disease pathology and immune cell infiltration into the CNS (
). S1P enhances TNFα-induced expression of the receptor activator of nuclear factor kB (RANK) ligand by these cells, an effect replicated in a synovial cell-like cell line, MH7 (
). In collagen-induced models of rheumatoid arthritis, a S1P1-specific antagonist prevented or ameliorated disease by upregulating lymphocyte CD69 expression, which downregulates S1P1 surface expression, blocking thymic egress (
S1P1 also affects other populations of T cells, such as T regulatory cells (Treg), which, as the name implies, play an important role in controlling immune responses and T memory cells (
). S1P1 suppresses Treg development via the AKT/mammalian target of rapamyacin pathway and affects their migration from the thymus and out of the periphery by counteracting CCR7 retention signals, similar to the mechanism regulating the egress of effector T cells from lymph nodes (
). In a specific subset of T memory cells, nonlymphoid resident memory cells (TRM), cytokines that induce the TRM phenotype also downregulate the transcription factor Krüppel-like factor2 and its target gene, S1pr1 (
). Subsequently, TRM are unable to sense S1P in circulation and are maintained in the periphery.
Although S1P1 has been the focus of much research, not much is known of the roles of the other S1PRs. In CD8 effector T cells, S1P4 may influence their trafficking to lymph nodes (LNs), although it appears not to be a primary regulator (
). S1pr4−/− mice have decreased Th17 T cell polarization; however, reduced Th17 differentiation is likely T cell extrinsic and primarily due to functions of S1P4 in dendritic cells (DCs) (
S1PR expression choreographs many aspects of B cell subset localization within lymphoid organs, thereby affecting their functionality; however, there are some direct effects of S1P signaling on B cell survival (Fig. 3) (
). While S1P1 has some regulatory functions in B cells, it appears that S1P2 has a greater impact on these cells. Aged S1pr2−/− mice develop diffuse large B cell lymphoma (DLBCL), characterized by increased germinal center (GC) B cells and spontaneous GC formation, which correlates with an approximate 26% mutation incidence for S1PR2 in human DLBCL (
). Additionally, trafficking of marginal zone (MZ) B cells between the MZ and the follicle is regulated by S1P1, which maintains these cells in the MZ in order for them to capture blood-borne antigens (
Studies of nonobese diabetic mice have shown that upregulation of S1P3 by MZ B cells and their T2 MZ precursors may also play a role in enhancing MZ retention in these mice (
Marginal-zone B-cells of nonobese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes, and present autoantigen to diabetogenic T-cells.
). However, it may be important for positioning of immature B cells and their progenitors within the BM, whereas S1P1 participates in directing their migration from the BM parenchyma into sinusoids and subsequently into circulation (
Natural killer (NK) cells are considered innate lymphoid cells that develop from lymphoid progenitors in the BM, but do not undergo genomic changes that occur in the B or T cell receptor genes (
). S1P5 normally antagonizes NK CXCR4 BM retention signals, and S1pr5−/− mice have decreased numbers of NK cells in the periphery and increased numbers in lymph nodes and BM due to defective migration (
). This phenotype is also observed in the mouse model of Niemann-Pick disease type C, a lysosomal storage disorder presenting as an accumulation of cholesterol and sphingolipids in the lysosome and decreased concentrations of circulating S1P in human patients (
). Studies utilizing FTY720 indicated that S1P1 also contributes to NK cell migration from LN to lymph, but the contribution is relatively minor compared with that of S1P5, which is not subject to CD69 regulation (
). Decidual NK (dNK) cells are a specialized NK cell subset that regulates trophoblast invasion during early pregnancy by secreting pro-angiogenic and growth factors, including vascular endothelial growth factor (VEGF) (
). S1PRs expressed by monocytes and macrophages regulate their migration and activation, and the receptors responsible are cell subtype- and situation-specific (Fig. 4). In general, S1P1 and S1P3 appear to induce migration toward S1P, whereas S1P2 expression repulses macrophages from S1P (
). S1pr2−/− mice on a pro-atherogenic genetic background (Apoe−/−) developed significantly less atherosclerosis, accompanied by decreased macrophage and monocyte retention in atherosclerotic plaques, indicating effects on migration, tissue retention, and activation (
). In comparison, S1pr3−/− mice on the same Apoe−/− background do not have altered development of atherosclerosis, but do have decreased monocytes and macrophages with atherosclerotic lesions (
). In WT mice, treatment with FTY720 results in decreased circulating monocytes; however, use of the S1P1/4/5 agonist, BAF312, yielded similar results, both at homeostasis and during EAE, indicating that S1P3 is not the sole regulator of monocyte circulation (
). This could be a cell subtype-specific effect, or dependent on environment, as local administration of FTY720 appeared to enhance recruitment of anti-inflammatory pro-angiogenic monocytes (
Fig. 4Expression of S1PRs and responses by cells of the innate immune system. Monocytes and/or macrophages express S1P1–4, neutrophils express S1P1, S1P3, and S1P4, eosinophils and MCs express all S1PRs, and DCs express S1P1, S1P3, and S1P4. Cells do not necessarily express all of the illustrated S1PRs at one time, but may have differential expression during different stages of maturation or activation.
A report utilizing the zymosan peritonitis model proposed that the resulting apoptotic neutrophils induced S1P1 expression on recruited macrophages and that S1P1 is necessary for emigration from the inflamed peritoneum, but has no role in efferocytosis or activation (
). S1P2 on alveolar macrophages may regulate their phagocytic capacity, as S1pr2−/− alveolar macrophages displayed decreased phagocytosis of the fungus Cryptococcus neoformans due to decreased expression of Fc receptors necessary for phagocytosis of antibody-opsonized fungus (
). Neutrophils express mRNA for all S1PRs; however, the level of expression and the ability of S1P to affect changes in their responses depend upon their activation status (Fig. 4) (
). Although S1P4 deficiency in Sgpl knockouts resulted in circulating neutrophil numbers that were close to WT, S1P4 was not specifically deleted in neutrophils, raising the possibility that multiple cell types were responsible for the effect. Specific deletion of neutrophil S1P1 did not normalize neutrophil numbers in Sgpl−/− mice. However, in rat models of hyperalgesia dependent upon neutrophil infiltration, S1P1 was necessary for neutrophil recruitment (
). Eosinophils from mice over-expressing interleukin-5, an eosinophil growth factor, express high levels of S1P3 and demonstrate increased chemotactic responses to S1P in vitro (Fig. 4) (
). In a model of allergic rhinitis, FTY720 treatment significantly decreased the numbers of infiltrating MCs and eosinophils, resulting in resolution (
). Similar to lymphocytes, S1P1 regulates MC migration toward the antigen, whereas S1P2 regulates their activation status upon FcεRI ligation, inducing degranulation and CCL2 secretion (
Sphingosine 1-phosphate induces chemotaxis of immature and modulates cytokine-release in mature human dendritic cells for emergence of Th2 immune responses.
Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3.
). In EAE, although S1P1 agonism decreased disease pathology, it did not affect entry into the CNS of a subset of DCs (plasmacytoid DCs). However, plasmacytoid DCs in the CNS were necessary for the efficacy of S1P1 agonist treatment (
). In models of autoimmune disease, Th2-type immune responses such as allergic airway inflammation and cutaneous hypersensitivity, S1pr4−/− mice had increased pathology and up to 50% increase in DCs in draining LN after topical antigen application (
). S1P regulates embryonic nervous system development, as the neuroepithelial layers of the developing telencephalon in S1pr1−/− embryos have significantly increased apoptosis and decreased mitosis (
). S1P2 may also play a role in regulating neural progenitors, as postischemic administration of the S1P2 antagonist JTE-013 or short hairpin RNA against S1P2 significantly increased progenitor migration to the ischemic region (
). This indicates that S1P2 may repel neural progenitors from areas of high S1P concentration in the same manner as it regulates macrophage migration (
). Interestingly, neural stem cells were protected from radiation-induced apoptosis by nanomolar FTY720 treatment in vitro, although it is unknown which receptor is involved in this protection (
Fig. 5Expression of S1PRs and responses by neural cells. Neural progenitors express S1P1 and S1P2, neurons express S1P1 and S1P3, oligodendrocytes express S1P1 and S1P5, and astrocytes express S1P1 and S1P2. S1P1 couples exclusively to Gαi. S1P2 and S1P3 can couple to Gαi, Gα12/13, or Gαq, and S1P5 can couple to Gαi or Gα12/13. Cells do not necessarily express all of the illustrated S1PRs at one time, but may have differential expression during different stages of maturation or activation.
Although analyses of entire mouse dorsal root ganglion found that S1P3 was the most highly expressed S1PR, single cell mRNA analysis of individual neurons found that S1P1 was most highly expressed, regardless of neuronal subtype, indicating that high expression of S1P3 occurs in ganglion cell types other than neurons (Fig. 5) (
). One group found that pain responses induced by intradermal S1P injection or models of postoperative pain were significantly decreased in S1pr3−/− mice, whereas minimal differences were seen in S1pr1−/− mice (
). Finally, in the murine model of the neurodevelopmental disease, Rett syndrome, FTY720 or S1P1-specific agonist SEW2871 in vivo treatment increased neuron production of brain-derived neurotrophic factor and decreased neurological symptoms (
). Process retraction, Rho/ROCK-mediated inhibition of immature oligodentrocyte precursor migration, and Gi/AKT-mediated survival in mature oligodendrocytes occurs via S1P5 (Fig. 5) (
). Ex vivo studies using cerebellar slice cultures indicated that S1PR agonism, particularly S1P1, could prevent or reverse demyelination, explaining the ability of FTY720 to induce remyelination and process extension in the same system (
). Data from a different in vitro system, myelinated neurospheres, indicated that FTY720 decreased microglial activation and oligodenrocyte apoptosis, and induced remyelination primarily by S1P5 agonism (
). An in vivo study provides conflicting evidence to these in vitro studies, reporting no effects on myelin repair with FTY720 treatment; however, the models of demyelination utilized in both the in vitro and in vivo studies were induced chemically and were meant to exclude possible effects of immune or vascular cells (
). As such, they cannot model complex neuroinflammatory disease and care must therefore be taken when attempting to extrapolate results to in vivo disease, such as EAE or MS.
The resident immune cells of the CNS, microglia, express all S1PRs (
). In vitro studies indicated that FTY720 downregulated production of pro-inflammatory molecules by microglia while increasing neurotrophic factor production, resulting in an overall neuroprotective phenotype (
). FTY720 also inhibited secretory vesicle mobility and exocytic release by astroglia, thus inhibiting the release of pro-inflammatory mediators by this cell type, as well (
). In vivo, specific deletion of astrocyte S1P1 resulted in decreased EAE pathology and a loss of FTY720 efficacy, indicating that the primary target of FTY720 during EAE was S1P1 specifically on astrocytes (
). Additionally, in a model of spinal cord injury, FTY720 affected the later stages of vascular permeability and astrogliosis, partially through agonism of S1P1 (
). Another target of FTY720, S1P3, was also found on reactive astrocytes in human MS lesions and upregulated by lipopolysaccharide stimulation of astrocytes in vitro, although it is unknown if expression of S1P3 is protective or pathogenic in the context of MS/EAE (
). Mice deficient in the one S1PR not targeted by FTY720, S1P2, are prone to seizures resulting in 40% mortality and have enhanced hippocampal gliosis accompanied by behavioral defects (
). Importantly, MS patients treated with fingolimod show reduced brain volume loss and lesional activity, suggesting the importance of S1PR pathways in neuroprotection (
Brain volume changes, on-study correlations and the link to disability in three fingolimod phase 3 studies (Abstract in 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. Copenhagen,
Denmark2013: 2-5
Relapse rates and disability remain consistently low with long-term fingolimod therapy: five year interim results of the LONGTERMS extension study (Abstract in 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. Copenhagen,
Denmark2013: 2-5
The blood brain barrier (BBB) forms through unique interactions between brain endothelial cells, astrocyte foot-processes, and pericytes, and regulates interactions between the immune and nervous systems (
). S1P5 was highly expressed by human brain capillary endothelial cells, and antagonism of S1P5 in an in vitro model of BBB decreased vascular permeability and monocytic transmigration (
). Studies of FTY720 treatment in the context of transient cerebral ischemia and reperfusion have demonstrated neuroprotection in mouse and rat models; however, these effects may be due to effects on interactions between the neurovasculature and immune cells (
). FTY720 treatment reduced brain edema as well as expression of the vascular adhesion molecule, ICAM-1, resulting in decreased neutrophil infiltration (
). Additionally, when transient cerebral ischemia was induced in lymphocyte-deficient Rag1−/− mice, the protective effect of FTY720 was lost, further implying that FTY720-mediated protection is due to effects on the neurovasculature and its interactions with immune cells (
). Conversely, a study utilizing a model of permanent cerebral ischemia demonstrated no effect on pathology with FTY720 treatment, whereas another group demonstrated efficacy after delaying FTY720 treatment for 3 days after photothrombosis induction, with increased functional capacity and decreased astrogliosis (
). Thus, protection by FTY720 may be dependent on the method of ischemia induction and temporal regulation of cell activation and recruitment.
INVOLVEMENT OF S1PRs IN CANCER AND ONCOGENESIS
S1PRs have also been implicated in cancer pathogenesis, playing roles in tumor maintenance similar to their roles in maintenance of homeostasis, such as modulation of survival and proliferation (
). WT hamster lung fibroblasts were protected from nutrient deprivation-induced apoptosis by expression of S1P1, which induced the anti-apoptotic protein Mcl1 via the phosphoinositide 3-kinase and PKC pathways (
). Lung adenocarcinoma cell lines respond to S1P with increased proliferation and invasion through S1P3-mediated expression of epidermal growth factor receptor (EGFR) (
Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1.
). High expression of S1P1 or S1P3 by ER+ breast cancer cells correlated with poor prognosis and high S1P1 expression induced decreased expression of pro-apoptotic markers (
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.
Identification of novel functional and spatial associations between sphingosine kinase 1, sphingosine 1-phosphate receptors and other signaling proteins that affect prognostic outcome in estrogen receptor-positive breast cancer.
). In a model of ulcerative colitis, considered a possible precursor for colon cancer, increased colonic bleeding and mortality resulted from S1P1 deletion (
). In a model of colitis-associated cancer, S1P1 signaling was necessary for persistent activation of nuclear factor-kB and signal transducer and activator of transcription3 transcription factors needed for maintaining the chronic inflammatory state and could be blocked by FTY720 treatment (
). In human colon cancer cells, expression of the chemotherapeutic resistance and cancer stem cell marker CD44 was regulated by S1P2-induced ERK phosphorylation (
Sphingosine kinase 1 plays a role in the upregulation of CD44 expression through extracellular signal-regulated kinase signaling in human colon cancer cells.
). Interestingly, FTY720 treatment impaired the mucosal immune response to the extracellular bacterium, Citrobacter rodentium, including decreased DC numbers, as well as macrophages and T cells in the colon, while increasing bacterial burden (
). AKT and Bcl-associated death promoter pro-survival pathways were also reduced by FTY720 administration to neuroblastoma cells in an in vitro and an in vivo xenograft model, resulting in decreased cancer cell viability (
FTY720 inhibits tumor growth and enhances the tumor-suppressive effect of topotecan in neuroblastoma by interfering with the sphingolipid signaling pathway.
S1PR expression in several hematological malignancies has also been described, including S1P1 expression by classical Hodgkin's lymphoma (CHL) cells, B cell chronic lymphocytic leukemia (B-CLL) cells, and activated B cell-like DLBCL cells (
). Chronic myeloid leukemia (CML) cells expressed S1P2, which resulted in increased stability of the B cell receptor-Abl1 fusion protein and subsequently, increased proliferation (
). Expression of S1PRs by blood cancer cells may directly regulate their survival or by controlling the localization of cells within permissive environments such as the lymph nodes.
CONCLUDING REMARKS
S1PRs are gaining appreciation as powerful modulators of homeostasis and pathogenesis. In all biological systems, S1PRs play some role in regulating cell survival, migration, phenotype, activation status, and proliferation. In the current review, we have attempted to summarize the most recent advances in the field of S1PR biology and to provide novel insights into the biological responses regulated. As more cell-specific animal models of gene deletion or over-expression are created, and agonists and antagonists with greater S1PR subtype specificity are developed, further studies with such tools will clarify the contributions of specific S1PRs in each physiological or pathological context. This is especially true of the less explored members of the S1PR family, S1P4 and S1P5. Additionally, we anticipate that the development of more compounds for clinical use will expand our understanding of the complex signaling networks regulated by S1PRs and their role in human homeostasis and disease.
REFERENCES
Blaho V.A.
Hla T.
Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors.
Sphingosine 1-phosphate is a blood constituent released from activated platelets, possibly playing a variety of physiological and pathophysiological roles.
Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: results from a 12-week, open-label pilot study in multiple sclerosis patients.
Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor-null mice and pharmacological tools.
An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors.
Marginal-zone B-cells of nonobese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes, and present autoantigen to diabetogenic T-cells.
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