scholarly journals Sphingosine 1-phosphate: Lipid signaling in pathology and therapy

Science ◽  
2019 ◽  
Vol 366 (6463) ◽  
pp. eaar5551 ◽  
Author(s):  
Andreane Cartier ◽  
Timothy Hla
Keyword(s):  
Immune Cell ◽  
Clinical Medicine ◽  
Lipid Mediator ◽  
Cell Trafficking ◽  
Multidisciplinary Research ◽  
Adaptive Immune ◽  
The Past ◽  
Sphingosine 1 Phosphate ◽  
Fibrotic Diseases ◽  
G Protein Coupled

Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein–coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.

Phase II trial of opaganib in patients with metastatic castration-resistant prostate cancer progressing on abiraterone or enzalutamide (NCT04207255).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS191-TPS191
Author(s):  
Omer Kucuk ◽  
Charles Smith ◽  
Terry Plasse ◽  
Besim Ogretmen ◽  
Shikhar Mehrotra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Modulation ◽  
Immune Cell ◽  
Progression Free Survival ◽  
Competitive Inhibitor ◽  
Cell Trafficking ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
Sphingosine 1 Phosphate

TPS191 Background: Opaganib (Yeliva, ABC294640) is a first-in-class, sphingosine kinase-2 (SK2) selective inhibitor, with anticancer, anti-inflammatory and anti-viral activities. SK2, a lipid kinase catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, opaganib blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Opaganib is a sphingosine-competitive inhibitor of SK2 and also inhibits dihydroceramide desaturase. Opaganib has antitumor activity against human and murine prostate cancer cell lines, and in xenograft (LNCaP) and syngeneic (MycCAP, TRAMP-C1) murine tumor models. In addition to its target effect of reducing sphingosine-1-phosphate, opaganib reduces both MYC and AR proteins through its kinase-blocking and desaturase-inhibiting properties, respectively. Methods: The study is open to patients with mCRPC who have been treated with at least one newer androgen antagonist (abiraterone or enzalutamide) and no prior chemotherapy for castration-resistant disease. Patients who are failing either abiraterone or enzalutamide may enroll, with the addition of opaganib. The trial design includes brief safety lead-in cohort 1a (abiraterone + opaganib 250 mg Q 12hr, 3/3 enrolled) and 1b (enzalutamide + opaganib 250 mg Q 12hr, 3/3 enrolled). These cohorts have been completed without any DLTs. We are now enrolling cohort 2 (abiraterone + opaganib 500 mg Q 12hr, 0/27 enrolled) and cohort 3 (enzalutamide + opaganib 500 mg Q 12hr, 8/27 enrolled). A total of 60 patients will be enrolled and response will be evaluated after 4 cycles (28 days/cycle) using a composite metric based on PSA, bone scan and RECIST measurements per PCWG3 criteria. Safety and tolerability will be monitored, and dose modifications will be allowed. Primary endpoint is disease control (stable disease or better) after 4 cycles. Secondary endpoints include overall survival, radiographic progression-free survival and PSA progression-free survival. Correlative studies include assessment of quality of life (QOL), circulating MDSCs, immune cells and clones with amplified AR or MYC. Supported by NIH grant P01 CA203628. Clinical trial information: NCT04207255.

scholarly journals Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient

2006 ◽  
Vol 397 (3) ◽  
pp. 461-471 ◽  
Author(s):  
Krishnan Venkataraman ◽  
Shobha Thangada ◽  
Jason Michaud ◽  
Myat Lin Oo ◽  
Youxi Ai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Immune Cell ◽  
Umbilical Vein ◽  
Wild Type Mouse ◽  
Receptor Internalization ◽  
Lipid Mediator ◽  
Cell Trafficking ◽  
Hek 293 ◽  
Human Embryonic Kidney Cells ◽  
Mouse Plasma

Sphingosine 1-phosphate (S1P), produced by Sphks (sphingosine kinases), is a multifunctional lipid mediator that regulates immune cell trafficking and vascular development. Mammals maintain a large concentration gradient of S1P between vascular and extravascular compartments. Mechanisms by which S1P is released from cells and concentrated in the plasma are poorly understood. We recently demonstrated [Ancellin, Colmont, Su, Li, Mittereder, Chae, Stefansson, Liau and Hla (2002) J. Biol. Chem. 277, 6667–6675] that Sphk1 activity is constitutively secreted by vascular endothelial cells. In the present study, we show that among the five Sphk isoforms expressed in endothelial cells, the Sphk-1a isoform is selectively secreted in HEK-293 cells (human embryonic kidney cells) and human umbilical-vein endothelial cells. In sharp contrast, Sphk2 is not secreted. The exported Sphk-1a isoform is enzymatically active and produced sufficient S1P to induce S1P receptor internalization. Wild-type mouse plasma contains significant Sphk activity (179 pmol·min−1·g−1). In contrast, Sphk1−/− mouse plasma has undetectable Sphk activity and approx. 65% reduction in S1P levels. Moreover, human plasma contains enzymatically active Sphk1 (46 pmol·min−1·g−1). These results suggest that export of Sphk-1a occurs under physiological conditions and may contribute to the establishment of the vascular S1P gradient.

scholarly journals S1P and the birth of platelets

2012 ◽  
Vol 209 (12) ◽  
pp. 2137-2140 ◽  
Author(s):  
Timothy Hla ◽  
Sylvain Galvani ◽  
Shahin Rafii ◽  
Ralph Nachman
Keyword(s):  
Therapeutic Strategy ◽  
Lipid Mediator ◽  
Cell Trafficking ◽  
Biological Functions ◽  
Platelet Production ◽  
S1p1 Receptor ◽  
Sphingosine 1 Phosphate ◽  
Trafficking Organization ◽  
Cxcr4 Axis ◽  
Novel Therapeutic

Recent work has highlighted the multitude of biological functions of sphingosine 1-phosphate (S1P), which include roles in hematopoietic cell trafficking, organization of immune organs, vascular development, and neuroinflammation. Indeed, a functional antagonist of S1P1 receptor, FTY720/Gilenya, has entered the clinic as a novel therapeutic for multiple sclerosis. In this issue of the JEM, Zhang et al. highlight yet another function of this lipid mediator: thrombopoiesis. The S1P1 receptor is required for the growth of proplatelet strings in the bloodstream and the shedding of platelets into the circulation. Notably, the sharp gradient of S1P between blood and the interstitial fluids seems to be essential to ensure the production of platelets, and S1P appears to cooperate with the CXCL12–CXCR4 axis. Pharmacologic modulation of the S1P1 receptor altered circulating platelet numbers acutely, suggesting a potential therapeutic strategy for controlling thrombocytopenic states. However, the S1P4 receptor may also regulate thrombopoiesis during stress-induced accelerated platelet production. This work reveals a novel physiological action of the S1P/S1P1 duet that could potentially be harnessed for clinical translation.

Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances

Gut ◽  
2019 ◽  
Vol 68 (9) ◽  
pp. 1688-1700 ◽  
Author(s):  
Sebastian Zundler ◽  
Emily Becker ◽  
Lisa Lou Schulze ◽  
Markus F Neurath
Keyword(s):  
Immune Cell ◽  
Cell Trafficking ◽  
T Cell Trafficking ◽  
Immune Cell Trafficking ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Immune Cell Subpopulations ◽  
Cell Subpopulations ◽  
G Protein Coupled ◽  
Lymphocyte Populations

Intestinal immune cell trafficking has been identified as a central event in the pathogenesis of inflammatory bowel diseases (IBD). Intensive research on different aspects of the immune mechanisms controlling and controlled by T cell trafficking and retention has led to the approval of the anti-α4β7 antibody vedolizumab, the ongoing development of a number of further anti-trafficking agents (ATAs) such as the anti-β7 antibody etrolizumab or the anti-MAdCAM-1 antibody ontamalimab and the identification of potential future targets like G-protein coupled receptor 15. However, several aspects of the biology of immune cell trafficking and regarding the mechanism of action of ATAs are still unclear, for example, which impact these compounds have on the trafficking of non-lymphocyte populations like monocytes and how precisely these therapies differ with regard to their effect on immune cell subpopulations. This review will summarise recent advances of basic science in the field of intestinal immune cell trafficking and discuss these findings with regard to different pharmacological approaches from a translational perspective.

scholarly journals Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate

2012 ◽  
Vol 447 (1) ◽  
pp. 149-157 ◽  
Author(s):  
Yugesh Kharel ◽  
Mithun Raje ◽  
Ming Gao ◽  
Amanda M. Gellett ◽  
Jose L. Tomsig ◽  
...  
Keyword(s):  
G Protein Coupled Receptors ◽  
Lipid Mediator ◽  
Wild Type ◽  
Downstream Effects ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
And Migration ◽  
G Protein Coupled ◽  
Hybrid Mice

S1P (sphingosine 1-phosphate) is a pleiotropic lipid mediator involved in numerous cellular and physiological functions. Of note among these are cell survival and migration, as well as lymphocyte trafficking. S1P, which exerts its effects via five GPCRs (G-protein-coupled receptors) (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases). Although SphK1 is the more intensively studied isotype, SphK2 is unique in it nuclear localization and has been reported to oppose some of the actions ascribed to SphK1. Although several scaffolds of SphK1 inhibitors have been described, there is a scarcity of selective SphK2 inhibitors that are necessary to evaluate the downstream effects of inhibition of this isotype. In the present paper we report a cationic amphiphilic small molecule that is a selective SphK2 inhibitor. In the course of characterizing this compound in wild-type and SphK-null mice, we discovered that administration of the inhibitor to wild-type mice resulted in a rapid increase in blood S1P, which is in contrast with our SphK1 inhibitor that drives circulating S1P levels down. Using a cohort of F2 hybrid mice, we confirmed, compared with wild-type mice, that circulating S1P levels were higher in SphK2-null mice and lower in SphK1-null mice. Thus both SphK1 and SphK2 inhibitors recapitulate the blood S1P levels observed in the corresponding null mice. Moreover, circulating S1P levels mirror SphK2 inhibitor levels, providing a convenient biomarker of target engagement.

scholarly journals Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application

2015 ◽  
Vol 396 (6-7) ◽  
pp. 795-802 ◽  
Author(s):  
Matthias Schröder ◽  
Olga Arlt ◽  
Helmut Schmidt ◽  
Andrea Huwiler ◽  
Carlo Angioni ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cells ◽  
Subcellular Distribution ◽  
Immune Cell ◽  
Lipid Mediator ◽  
Sphingosine Kinase 2 ◽  
Relapsing Remitting ◽  
Sphingosine 1 Phosphate ◽  
Original Cell ◽  
Relapsing Remitting Multiple Sclerosis

Abstract FTY720 (Fingolimod; Gilenya®) is an immune-modulatory prodrug which, after intracellular phosphorylation by sphingosine kinase 2 (SphK2) and export, mimics effects of the endogenous lipid mediator sphingosine-1-phosphate. Fingolimod has been introduced to treat relapsing-remitting multiple sclerosis. However, little has been published about the immune cell membrane penetration and subcellular distribution of FTY720 and FTY720-P. Thus, we applied a newly established LC-MS/MS method to analyze the subcellular distribution of FTY720 and FTY720-P in subcellular compartments of spleen cells of wild type, SphK1- and SphK2-deficient mice. These studies demonstrated that, when normalized to the original cell volume and calculated on molar basis, FTY720 and FTY720-P dramatically accumulated several hundredfold within immune cells reaching micromolar concentrations. The amount and distribution of FTY720 was differentially affected by SphK1- and SphK2-deficiency. On the background of recently described relevant intracellular FTY720 effects in the nanomolar range and the prolonged application in multiple sclerosis, this data showing a substantial intracellular accumulation of FTY720, has to be considered for benefit/risk ratio estimates.

scholarly journals Effects of Immunomodulatory Drug Fingolimod (FTY720) on Chlamydia Dissemination and Pathogenesis

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Zengzi Zhou ◽  
Lingxiang Xie ◽  
Luying Wang ◽  
Min Xue ◽  
Dabao Xu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Gastrointestinal Tract ◽  
Genital Tract ◽  
Immune Cell ◽  
Cell Trafficking ◽  
Rectal Swabs ◽  
Sphingosine 1 Phosphate ◽  
Immunomodulatory Drug ◽  
Live Organism

ABSTRACT Fingolimod (FTY720), an FDA-approved immunomodulatory drug for treating multiple sclerosis, is an agonist of sphingosine-1-phosphate receptor (S1PR), which has been used as a research tool for inhibiting immune cell trafficking. FTY720 was recently reported to inhibit Chlamydia dissemination. Since genital Chlamydia spreading to the gastrointestinal tract correlated with its pathogenicity in the upper genital tract, we evaluated the effect of FTY720 on chlamydial pathogenicity in the current study. Following an intravaginal inoculation, live chlamydial organisms were detected in mouse rectal swabs. FTY720 treatment significantly delayed live organism shedding in the rectal swabs. However, FTY720 failed to block chlamydial spreading to the gastrointestinal tract. The live chlamydial organisms recovered from rectal swabs reached similar levels between mice with or without FTY720 treatment by day 42 in C57BL/6J and day 28 in CBA/J mice, respectively. Thus, genital Chlamydia is able to launch a 2nd wave of spreading via an FTY720-resistant pathway after the 1st wave of spreading is inhibited by FTY720. As a result, all mice developed significant hydrosalpinx. The FTY720-resistant spreading led to stable colonization of chlamydial organisms in the colon. Consistently, FTY720 did not alter the colonization of intracolonically inoculated Chlamydia. Thus, we have demonstrated that, following a delay in chlamydial spreading caused by FTY720, genital Chlamydia is able to both spread to the gastrointestinal tract via an FTY720-resistant pathway and maintain its pathogenicity in the upper genital tract. Further characterization of the FTY720-resistant pathway(s) explored by Chlamydia for spreading to the gastrointestinal tract may promote our understanding of Chlamydia pathogenic mechanisms.

scholarly journals Filamin A Expression Negatively Regulates Sphingosine-1-Phosphate-Induced NF-κB Activation in Melanoma Cells by Inhibition of Akt Signaling

2015 ◽  
pp. MCB.00554-15 ◽  
Author(s):  
Ludmila Campos ◽  
Yamila Rodriguez ◽  
Andreia Machado Leopoldino ◽  
Nitai C. Hait ◽  
Pablo Lopez Bergami ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Melanoma Cells ◽  
Lipid Mediator ◽  
Filamin A ◽  
Necrosis Factor Alpha ◽  
Akt Activation ◽  
Sphingosine 1 Phosphate ◽  
Negative Role ◽  
Factor Alpha ◽  
G Protein Coupled

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that regulates many processes in inflammation and cancer. S1P is a ligand for five G protein-coupled receptors, S1PR1-5, and also has important intracellular actions. Previously we have shown that intracellular S1P is involved in tumor necrosis factor alpha (TNF)-induced NF-κB activation in melanoma cell lines that express filamin A (FLNA). Here, we show that extracellular S1P activates NF-κB only in melanoma cells that lack FLNA. In these cells S1P, but not TNF, promotes IKK and p65 phosphorylation, IκBα degradation, p65 nuclear translocation and NF-κB reporter activity. NF-κB activation induced by S1P was mediated via S1PR1 and S1PR2. Exogenous S1P enhanced phosphorylation of PKCδ and its downregulation reduced S1P-induced phosphorylation of IKK and p65. In addition, silencing of Bcl10 also inhibited S1P-induced IKK phosphorylation. Surprisingly, S1P reduced Akt activation in melanoma cells that express FLNA, whereas in the absence of FLNA, high phosphorylation levels of Akt were maintained, enabling S1P-mediated NF-κB signaling. In accord, inhibition of Akt suppressed S1P-mediated IKK and p65 phosphorylation and degradation of IκBα. Hence, these results support a negative role of FLNA in S1P-mediated NF-κB activation in melanoma cells through modulation of Akt.

scholarly journals S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling

2017 ◽  
Vol 2017 ◽  
pp. 1-19 ◽  
Author(s):  
Ashok Kumar ◽  
Jesus Zamora-Pineda ◽  
Emilie Degagné ◽  
Julie D. Saba
Keyword(s):  
Immune Cell ◽  
Current Evidence ◽  
Cell Trafficking ◽  
Inherited Disease ◽  
Gene Encoding ◽  
Surface Receptors ◽  
Sphingosine 1 Phosphate ◽  
Lymphocyte Egress ◽  
S1p Lyase ◽  
Inherited Mutations

Sphingosine-1-phosphate (S1P) is a potent lipid signaling molecule that regulates pleiotropic biological functions including cell migration, survival, angiogenesis, immune cell trafficking, inflammation, and carcinogenesis. It acts as a ligand for a family of cell surface receptors. S1P concentrations are high in blood and lymph but low in tissues, especially the thymus and lymphoid organs. S1P chemotactic gradients are essential for lymphocyte egress and other aspects of physiological cell trafficking. S1P is irreversibly degraded by S1P lyase (SPL). SPL regulates lymphocyte trafficking, inflammation and other physiological and pathological processes. For example, SPL located in thymic dendritic cells acts as a metabolic gatekeeper that controls the normal egress of mature T lymphocytes from the thymus into the circulation, whereas SPL deficiency in gut epithelial cells promotes colitis and colitis-associated carcinogenesis (CAC). Recently, we identified a complex syndrome comprised of nephrosis, adrenal insufficiency, and immunological defects caused by inherited mutations in human SGPL1, the gene encoding SPL. In the present article, we review current evidence supporting the role of SPL in thymic egress, inflammation, and cancer. Lastly, we summarize recent progress in understanding other SPL functions, its role in inherited disease, and SPL targeting for therapeutic purposes.

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