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Sphingosine 1-phosphate receptor expression profile and regulation of migration in human thyroid cancer cells.

ABSTRACT: S1P (sphingosine 1-phosphate) receptor expression and the effects of S1P on migration were studied in one papillary (NPA), two follicular (ML-1, WRO) and two anaplastic (FRO, ARO) thyroid cancer cell lines, as well as in human thyroid cells in primary culture. Additionally, the effects of S1P on proliferation, adhesion and calcium signalling were addressed in ML-1 and FRO cells. All cell types expressed multiple S1P receptors. S1P evoked intracellular calcium signalling in primary cultures, ML-1 cells and FRO cells. Neither proliferation nor migration was affected in primary cultures, whereas S1P partly inhibited proliferation in ML-1 and FRO cells. Low nanomolar concentrations of S1P inhibited migration in FRO, WRO and ARO cells, but stimulated ML-1 cell migration. Consistently, S1P1 and S1P3, which mediate migratory responses, were strongly expressed in ML-1 cells, and S1P2, which inhibits migration, was the dominating receptor in the other cell lines. The migratory effect in ML-1 cells was mediated by G(i) and phosphatidylinositol 3-kinase. Both S1P and the S1P1-specific agonist SEW-2871 induced Akt phosphorylation at Ser473. However, SEW-2871 failed to stimulate migration, whereas the S1P1/S1P3 antagonist VPC 23019 inhibited S1P-induced migration. The results suggest that aberrant S1P receptor expression may enhance thyroid cancer cell migration and thus contribute to the metastatic behaviour of some thyroid tumours.

SUBMITTER: Balthasar S

PROVIDER: S-EPMC1559461 | biostudies-other | 2006 Sep

REPOSITORIES: biostudies-other

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Sphingosine-1-phosphate/sphingosine-1-phosphate receptor 1 signaling is required for migration of naive human T cells from the thymus to the periphery.

Project description:BackgroundThe mechanisms that govern the egress of mature thymocytes from the human thymus to the periphery remain understudied yet are of utmost importance to the field of basic immunology, as well as T-cell reconstitution in various immunodeficiencies. We examined the expression and function of sphingosine-1-phosphate (S1P) receptors in human thymocyte egress.ObjectivesWe aimed to determine whether S1P receptors (S1P-Rs) play a role in mature human thymocyte egress and to identify the thymocyte population or populations that express S1P-Rs and respond to S1P by migrating across a concentration gradient.MethodsHuman thymocytes were exposed to S1P in Transwell plate migration assays coupled to flow cytometry to evaluate the response to S1P of thymocytes at different stages of maturation. Constitutive S1P-R expression was quantified by means of real-time PCR in sorted thymocyte subsets and flow cytometry. S1P-R1 and Kruppel-like factor 2 expression were monitored after S1P exposure by using flow cytometry and quantitative PCR.ResultsS1P-R1 was the prevalent S1P receptor on mature human thymocytes (CD3(hi)CD27(+)CD69(-)), the population that also demonstrated the greatest response to S1P in migration assays. Pretreatment with FTY720, an S1P-R1 nonselective modulator significantly reduced migration and suggested a role for S1P-R2 in retaining thymocytes in the tissue. Lastly, surface S1P-R1 expression, as well S1PR1 and Kruppel-like factor 2 (KLF2) transcripts, were significantly decreased in mature thymocytes on exposure to S1P.ConclusionMature human thymocytes rely on S1P-R1 to migrate toward S1P. Taken in the context of murine work demonstrating that S1P is required for thymocyte egress to the periphery, our data highlight a new key chemokine for human thymocyte egress.

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Sphingosine 1-Phosphate Receptor 2 Regulates the Migration, Proliferation, and Differentiation of Mesenchymal Stem Cells.

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Sphingosine-1-phosphate induces the migration of thyroid follicular carcinoma cells through the microRNA-17/PTK6/ERK1/2 pathway.

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Sphingosine-1-phosphate receptor 1 in classical Hodgkin lymphoma: assessment of expression and role in cell migration.

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Project description:Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and inflammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. However, this feedback regulation can be overcome by the inflammatory cytokines, TNF-α or interleukin 1β. This enables high LPA and ATX levels to coexist in inflammatory conditions. The results are discussed in terms of ATX regulation in wound healing and cancer.

| S-EPMC4442871 | biostudies-literature

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects.

Project description:Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR1 to S1PR5. Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects (MP4 65540 kb).

| S-EPMC7932974 | biostudies-literature

Simvastatin-induced sphingosine 1-phosphate receptor 1 expression is KLF2-dependent in human lung endothelial cells.

Project description:We have demonstrated that simvastatin and sphingosine 1-phosphate (S1P) both attenuate increased vascular permeability in preclinical models of acute respiratory distress syndrome. However, the underlying mechanisms remain unclear. As Krüppel-like factor 2 (KLF2) serves as a critical regulator for cellular stress response in endothelial cells (EC), we hypothesized that simvastatin enhances endothelial barrier function via increasing expression of the barrier-promoting S1P receptor, S1PR1, via a KLF2-dependent mechanism. S1PR1 luciferase reporter promoter activity in human lung artery EC (HPAEC) was tested after simvastatin (5 μM), and S1PR1 and KLF2 protein expression detected by immunoblotting. In vivo, transcription and expression of S1PR1 and KLF2 in mice lungs were detected by microarray profiling and immunoblotting after exposure to simvastatin (10 mg/kg). Endothelial barrier function was measured by trans-endothelial electrical resistance with the S1PR1 agonist FTY720-(S)-phosphonate. Both S1PR1 and KLF2 gene expression (mRNA, protein) were significantly increased by simvastatin in vitro and in vivo. S1PR1 promoter activity was significantly increased by simvastatin (P < 0.05), which was significantly attenuated by KLF2 silencing (siRNA). Simvastatin induced KLF2 recruitment to the S1PR1 promoter, and consequently, significantly augmented the effects of the S1PR1 agonist on EC barrier enhancement (P < 0.05), which was significantly attenuated by KLF2 silencing (P < 0.05). These results suggest that simvastatin upregulates S1PR1 transcription and expression via the transcription factor KLF2, and consequently augments the effects of S1PR1 agonists on preserving vascular barrier integrity. These results may lead to novel combinatorial therapeutic strategies for lung inflammatory syndromes.

| S-EPMC5448536 | biostudies-literature

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