Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1

2012 ◽  
Vol 444 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Mark E. Schnute ◽  
Matthew D. McReynolds ◽  
Tom Kasten ◽  
Matthew Yates ◽  
Gina Jerome ◽  
...  
Keyword(s):  
Potent Inhibitor ◽  
Inflammatory Diseases ◽  
Specific Inhibitor ◽  
Sphingosine Kinase ◽  
Head And Neck Carcinoma ◽  
High Rate ◽  
Neck Carcinoma ◽  
Sphingosine 1 Phosphate ◽  
Proportional Increase ◽  
And Migration

SphK (sphingosine kinase) is the major source of the bioactive lipid and GPCR (G-protein-coupled receptor) agonist S1P (sphingosine 1-phosphate). S1P promotes cell growth, survival and migration, and is a key regulator of lymphocyte trafficking. Inhibition of S1P signalling has been proposed as a strategy for treatment of inflammatory diseases and cancer. In the present paper we describe the discovery and characterization of PF-543, a novel cell-permeant inhibitor of SphK1. PF-543 inhibits SphK1 with a Ki of 3.6 nM, is sphingosine-competitive and is more than 100-fold selective for SphK1 over the SphK2 isoform. In 1483 head and neck carcinoma cells, which are characterized by high levels of SphK1 expression and an unusually high rate of S1P production, PF-543 decreased the level of endogenous S1P 10-fold with a proportional increase in the level of sphingosine. In contrast with past reports that show that the growth of many cancer cell lines is SphK1-dependent, specific inhibition of SphK1 had no effect on the proliferation and survival of 1483 cells, despite a dramatic change in the cellular S1P/sphingosine ratio. PF-543 was effective as a potent inhibitor of S1P formation in whole blood, indicating that the SphK1 isoform of sphingosine kinase is the major source of S1P in human blood. PF-543 is the most potent inhibitor of SphK1 described to date and it will be useful for dissecting specific roles of SphK1-driven S1P signalling.

scholarly journals δ-Catenin/NPRAP (neural plakophilin-related armadillo repeat protein) interacts with and activates sphingosine kinase 1

2004 ◽  
Vol 382 (2) ◽  
pp. 717-723 ◽  
Author(s):  
Toshitada FUJITA ◽  
Taro OKADA ◽  
Shun HAYASHI ◽  
Saleem JAHANGEER ◽  
Noriko MIWA ◽  
...  
Keyword(s):  
Cell Motility ◽  
Hippocampal Neurons ◽  
Mdck Cells ◽  
Specific Inhibitor ◽  
Sphingosine Kinase ◽  
Dependent Manner ◽  
Repeat Protein ◽  
Sphingosine 1 Phosphate ◽  
Key Enzyme ◽  
Armadillo Repeat

Sphingosine kinase (SPHK) is a key enzyme catalysing the formation of sphingosine 1-phosphate (SPP), a lipid messenger that is implicated in the regulation of a wide variety of important cellular events acting through intracellular, as well as extracellular, mechanisms. However, the molecular mechanism of intracellular actions of SPP remains unclear. Here, we have identified δ-catenin/NPRAP (neural plakophilin-related armadillo repeat protein) as a potential binding partner for SPHK1 by yeast two-hybrid screening. From co-immunoprecipitation analyses, the C-terminal portion of δ-catenin/NPRAP containing the seventh to tenth armadillo repeats was found to be required for interaction with SPHK1. Endogenous δ-catenin/NPRAP was co-localized with endogenous SPHK1 and transfected δ-catenin/NPRAP was co-localized with transfected SPHK1 in dissociated rat hippocampal neurons. MDCK (Madin–Darby canine kidney) cells stably expressing δ-catenin/NPRAP contained elevated levels of intracellular SPP. In a purified system δ-catenin/NPRAP stimulated SPHK1 in a dose-dependent manner. Furthermore, δ-catenin/NPRAP-induced increased cell motility in MDCK cells was completely inhibited by dimethylsphingosine, a specific inhibitor of SPHK1. These results strongly suggest that at least some of δ-catenin/NPRAP functions, including increased cell motility, are mediated by an SPHK–SPP signalling pathway.

scholarly journals The Expression of Sphingosine Kinase-1 in Head and Neck Carcinoma

2010 ◽  
Vol 192 (5) ◽  
pp. 314-324 ◽  
Author(s):  
María M. Facchinetti ◽  
Norberto A. Gandini ◽  
María E. Fermento ◽  
Norma B. Sterin-Speziale ◽  
Youngmi Ji ◽  
...  
Keyword(s):  
Head And Neck ◽  
Sphingosine Kinase ◽  
Head And Neck Carcinoma ◽  
Sphingosine Kinase 1 ◽  
Neck Carcinoma

scholarly journals Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate

2011 ◽  
Vol 440 (3) ◽  
pp. 345-353 ◽  
Author(s):  
Yugesh Kharel ◽  
Thomas P. Mathews ◽  
Amanda M. Gellett ◽  
Jose L. Tomsig ◽  
Perry C. Kennedy ◽  
...  
Keyword(s):  
Cell Survival ◽  
Sphingosine Kinase ◽  
Rapid Onset ◽  
Physiological Functions ◽  
Extracellular Signal ◽  
Signalling Molecule ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
And Migration

S1P (sphingosine 1-phosphate) is a signalling molecule involved in a host of cellular and physiological functions, most notably cell survival and migration. S1P, which signals via a set of five G-protein-coupled receptors (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases) from Sph (sphingosine). Interfering RNA strategies and SphK1 (sphingosine kinase type 1)-null (Sphk1−/−) mouse studies implicate SphK1 in multiple signalling cascades, yet there is a paucity of potent and selective SphK1 inhibitors necessary to evaluate the effects of rapid onset inhibition of this enzyme. We have identified a set of submicromolar amidine-based SphK1 inhibitors and report using a pair of these compounds to probe the cellular and physiological functions of SphK1. In so doing, we demonstrate that our inhibitors effectively lower S1P levels in cell-based assays, but we have been unable to correlate SphK1 inhibition with changes in cell survival. However, SphK1 inhibition did diminish EGF (epidermal growth factor)-driven increases in S1P levels and Akt (also known as protein kinase B)/ERK (extracellular-signal-regulated kinase) phosphorylation. Finally, administration of the SphK1 inhibitor to wild-type, but not Sphk1−/−, mice resulted in a rapid decrease in blood S1P levels indicating that circulating S1P is rapidly turned over.

Liver X receptor-α and miR-130a-3p regulate expression of sphingosine 1-phosphate receptor 2 in human umbilical vein endothelial cells

2016 ◽  
Vol 310 (3) ◽  
pp. C216-C226 ◽  
Author(s):  
Aihui Fan ◽  
Qian Wang ◽  
Yongjun Yuan ◽  
Jilun Cheng ◽  
Lixian Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Expression ◽  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
Specific Inhibitor ◽  
Barrier Dysfunction ◽  
Human Umbilical Vein ◽  
Tnf Α ◽  
Sphingosine 1 Phosphate ◽  
Umbilical Vein Endothelial Cells

Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signaling. Sphingosine 1-phosphate receptor 2 (S1PR2), an important inflammatory gene product, plays a role in the development of various inflammatory diseases. It was proposed that S1PR2 might be regulated by LXR-α. In the present study, the effect of LXR-α on tumor necrosis factor-α (TNF-α)-induced S1PR2 expression in human umbilical vein endothelial cells (HUVECs) was investigated and the underlying mechanism was explored. The results demonstrated that TNF-α led to an increase in S1PR2 expression and triggered a downregulation of LXR-α expression in HUVECs as well. Downregulation of LXR-α with specific small interfering RNA (siRNA) remarkably enhanced the primary as well as TNF-α-induced expression of S1PR2 in HUVECs. Activation of LXR-α by agonist GW3965 inhibited both primary and TNF-α-induced S1PR2 expression. GW3965 also attenuated S1PR2-induced endothelial barrier dysfunction. The data further showed that TNF-α induced a significant decrease in miR-130a-3p expression. Overexpression of miR-130a-3p with mimic product reduced S1PR2 protein expression, and inhibition of miR-130a-3p by specific inhibitor resulted in an increase in S1PR2 protein expression. Furthermore, activation of LXRs with agonist enhanced the expression of miR-130a-3p, and knockdown of LXR-α by siRNA suppressed miR-130a-3p expression. These results suggest that LXR-α might downregulate S1PR2 expression via miR-130a-3p in quiescent HUVECs. Stimulation of TNF-α attenuates the activity of LXR-α and results in enhanced S1PR2 expression.

scholarly journals Transcriptional Regulation of Sphingosine Kinase 1

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2437
Author(s):  
Joseph Bonica ◽  
Cungui Mao ◽  
Lina M. Obeid ◽  
Yusuf A. Hannun
Keyword(s):  
Transcriptional Regulation ◽  
Inflammatory Diseases ◽  
Second Messengers ◽  
Sphingosine Kinase ◽  
Transcriptional Level ◽  
Sphingosine Kinase 1 ◽  
Micro Rnas ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Expression And Activity

Once thought to be primarily structural in nature, sphingolipids have become increasingly appreciated as second messengers in a wide array of signaling pathways. Sphingosine kinase 1, or SK1, is one of two sphingosine kinases that phosphorylate sphingosine into sphingosine-1-phosphate (S1P). S1P is generally pro-inflammatory, pro-angiogenic, immunomodulatory, and pro-survival; therefore, high SK1 expression and activity have been associated with certain inflammatory diseases and cancer. It is thus important to develop an understanding of the regulation of SK1 expression and activity. In this review, we explore the current literature on SK1 transcriptional regulation, illustrating a complex system of transcription factors, cytokines, and even micro-RNAs (miRNAs) on the post transcriptional level.

scholarly journals S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense

Science ◽  
2018 ◽  
Vol 359 (6371) ◽  
pp. 114-119 ◽  
Author(s):  
Yuefeng Huang ◽  
Kairui Mao ◽  
Xi Chen ◽  
Ming-an Sun ◽  
Takeshi Kawabe ◽  
...  
Keyword(s):  
Host Defense ◽  
Tissue Repair ◽  
Inflammatory Diseases ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Sphingosine 1 Phosphate ◽  
Distant Tissue ◽  
Group 2 ◽  
And Migration ◽  
Interleukin 25

Innate lymphoid cells (ILCs) are innate counterparts of adaptive T lymphocytes, contributing to host defense, tissue repair, metabolic homeostasis, and inflammatory diseases. ILCs have been considered to be tissue-resident cells, but whether ILCs move between tissue sites during infection has been unclear. We show here that interleukin-25– or helminth-induced inflammatory ILC2s are circulating cells that arise from resting ILC2s residing in intestinal lamina propria. They migrate to diverse tissues based on sphingosine 1-phosphate (S1P)–mediated chemotaxis that promotes lymphatic entry, blood circulation, and accumulation in peripheral sites, including the lung, where they contribute to anti-helminth defense and tissue repair. This ILC2 expansion and migration is a behavioral parallel to the antigen-driven proliferation and migration of adaptive lymphocytes to effector sites and indicates that ILCs complement adaptive immunity by providing both local and distant tissue protection during infection.

scholarly journals Transactivation of Sphingosine-1–Phosphate Receptors by FcεRI Triggering Is Required for Normal Mast Cell Degranulation and Chemotaxis

2004 ◽  
Vol 199 (7) ◽  
pp. 959-970 ◽  
Author(s):  
Puneet S. Jolly ◽  
Meryem Bektas ◽  
Ana Olivera ◽  
Claudia Gonzalez-Espinosa ◽  
Richard L. Proia ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Sphingosine Kinase ◽  
Cross Linking ◽  
Cell Functions ◽  
Sphingosine 1 Phosphate ◽  
High Affinity Receptor ◽  
Affinity Receptor ◽  
And Migration ◽  
Cytoskeletal Rearrangements

Mast cells secrete various substances that initiate and perpetuate allergic responses. Cross-linking of the high-affinity receptor for IgE (FcεRI) in RBL-2H3 and bone marrow–derived mast cells activates sphingosine kinase (SphK), which leads to generation and secretion of the potent sphingolipid mediator, sphingosine-1–phosphate (S1P). In turn, S1P activates its receptors S1P1 and S1P2 that are present in mast cells. Moreover, inhibition of SphK blocks FcεRI-mediated internalization of these receptors and markedly reduces degranulation and chemotaxis. Although transactivation of S1P1 and Gi signaling are important for cytoskeletal rearrangements and migration of mast cells toward antigen, they are dispensable for FcεRI-triggered degranulation. However, S1P2, whose expression is up-regulated by FcεRI cross-linking, was required for degranulation and inhibited migration toward antigen. Together, our results suggest that activation of SphKs and consequently S1PRs by FcεRI triggering plays a crucial role in mast cell functions and might be involved in the movement of mast cells to sites of inflammation.

scholarly journals Sphingosine Kinase: A Novel Putative Target for the Prevention of Infection-Triggered Preterm Birth

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Vibhuti Vyas ◽  
Charles R. Ashby ◽  
Sandra E. Reznik
Keyword(s):  
Preterm Birth ◽  
Preterm Births ◽  
Sphingosine Kinase ◽  
The United States ◽  
High Rate ◽  
Survival Pathways ◽  
Extremely Preterm ◽  
Sphingosine 1 Phosphate ◽  
Potent Vasoconstrictor

Preterm birth is defined as any delivery before 37 complete weeks of gestation. It is a universal challenge in the field of obstetrics owing to its high rate of mortality, long-term morbidity, associated human suffering and economic burden. In the United States, about 12.18% deliveries in 2009 were preterm, producing an exorbitant cost of $5.8 billion. Infection-associated premature rupture of membranes (PROM) accounts for 40% of extremely preterm births (<28 weeks of gestation). Major research efforts are directed towards improving the understanding of the pathophysiology of preterm birth and ways to prevent or at least postpone delivery. Endothelin-1 (ET-1) is a potent vasoconstrictor that plays a significant role in infection-triggered preterm birth. Its involvement in a number of pathological mechanisms and its elevation in preterm delivered amniotic fluid samples implicate it in preterm birth. Sphingosine kinase (SphK) is a ubiquitous enzyme responsible for the production of sphingosine-1-phosphate (S1P). S1P acts as second messenger in a number of cell proliferation and survival pathways. SphK is found to play a key role in ET-1 mediated myometrial contraction. This review highlights SphK as a prospective target with great potential to prevent preterm birth.

Sphingosine 1-phosphate antagonizes apoptosis of human leukemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2828-2836 ◽  
Author(s):  
Olivier Cuvillier ◽  
Thierry Levade
Keyword(s):  
Cytochrome C ◽  
Acute Leukemia ◽  
Specific Inhibitor ◽  
Sphingosine Kinase ◽  
Serum Deprivation ◽  
Tumor Promoter ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Tnf Α ◽  
Sphingosine 1 Phosphate

Abstract Sphingosine 1-phosphate (S-1P) has been implicated as a second messenger preventing apoptosis by counteracting activation of executioner caspases. Here it is reported that S-1P prevents apoptosis and executioner caspase-3 activation by inhibiting the translocation of cytochrome c and Smac/DIABLO from mitochondria to the cytosol induced by anti-Fas, tumor necrosis factor-α (TNF-α), serum deprivation, and cell-permeable ceramides in the human acute leukemia Jurkat, U937, and HL-60 cell lines. Furthermore, the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate, which stimulates sphingosine kinase, the enzyme responsible for S-1P production, also inhibits cytochrome c and Smac/DIABLO release. In contrast, dimethylsphingosine (DMS), a specific inhibitor of sphingosine kinase, sensitizes cells to cytochrome c and Smac/DIABLO release triggered by anti-Fas, TNF-α, serum deprivation, or ceramide. DMS-induced mitochondrial apoptogenic factor leakage can likewise be overcome by S-1P cotreatment. Hence, S-1P, likely generated through a protein kinase C– mediated activation of sphingosine kinase, inhibits the apoptotic cascade upstream of the release of the mitochondrial apoptogenic factors, cytochrome c, and Smac/DIABLO in human acute leukemia cells.

Sign in / Sign up

Export Citation Format

Share Document