The Experts below are selected from a list of 7917 Experts worldwide ranked by ideXlab platform
Sarah Spiegel - One of the best experts on this subject based on the ideXlab platform.
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Sphingosine Kinase and Sphingosine-1-phosphate in liver pathobiology
Critical reviews in biochemistry and molecular biology, 2017Co-Authors: Timothy D. Rohrbach, Michael Maceyka, Sarah SpiegelAbstract:AbstractOver 20 years ago, Sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule. Subsequent studies later identified two related Kinases, Sphingosine Kinase 1 and 2, which are responsible for the phosphorylation of Sphingosine to S1P. Many stimuli increase Sphingosine Kinase activity and S1P production and secretion. Outside the cell, S1P can bind to and activate five S1P-specific G protein-coupled receptors (S1PR1–5) to regulate many important cellular and physiological processes in an autocrine or paracrine manner. S1P is found in high concentrations in the blood where it functions to control vascular integrity and trafficking of lymphocytes. Obesity increases blood S1P levels in humans and mice. With the world wide increase in obesity linked to consumption of high-fat, high-sugar diets, S1P is emerging as an accomplice in liver pathobiology, including acute liver failure, metabolic syndrome, control of blood lipid and glucose homeostasis, nonalcoholic fatty liver disease, a...
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Sphingosine Kinase: A Closer Look at Last
Structure (London England : 1993), 2013Co-Authors: Santiago Lima, Sarah SpiegelAbstract:Sphingosine-1-phosphate is a potent sphingolipid mediator, and the Kinase that produces it, Sphingosine Kinase 1 (SphK1), has been implicated in cancer progression, inflammation, and cardiovascular diseases. In this issue of Structure, Wang and colleagues provide the scientific community with the long awaited structure of SphK1.
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Regulation of p21 Expression by Sphingosine Kinase 2
The FASEB Journal, 2009Co-Authors: Nitai C. Hait, Sheldon Milstien, Sarah SpiegelAbstract:Sphingosine-1-phosphate (S1P) is a potent sphingolipid mediator formed by phosphorylation of Sphingosine catalyzed by two Sphingosine Kinase (SphK) isoenzymes, SphK1 and SphK2. Whereas SphK1 is ove...
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Activation of Sphingosine Kinase 1
Sphingolipid Biology, 2006Co-Authors: Michael Maceyka, Sheldon Milstien, Sergio E. Alvarez, Sarah SpiegelAbstract:Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that regulates many important biological processes as a ligand for cell surface receptors and as an intracellular second messenger. S1P levels inside cells are regulated in a temporal and spatial manner by the balance between its formation, catalyzed by two Sphingosine Kinase isoenzymes, SphK1 and SphK2, and degradation by S1P lyase and S1P-specific phosphatases. Activation of SphK1 is a key step in the agonist-induced regulation of S1P levels. SphK1 is a cytosolic enzyme and a growing body of evidence suggests that S1P production is also regulated by the translocation of SphK1 to membranes, where its substrate Sphingosine is formed. SphK1 translocation to membranes can be mediated by interactions with lipids and proteins. Here we review the current knowledge of SphK1 activation and translocation.
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Involvement of Sphingosine Kinase in TNF-α-stimulated Tetrahydrobiopterin Biosynthesis in C6 Glioma Cells
The Journal of biological chemistry, 2002Co-Authors: Lewis R. Vann, Sarah Spiegel, Lisa C Edsall, Shawn G. Payne, Sharon Twitty, Sheldon MilstienAbstract:In C6 glioma cells, the sphingolipid second messenger ceramide potentiates expression of inducible nitric-oxide synthase (iNOS) induced by tumor necrosis factor alpha (TNF-alpha) without affecting GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in the biosynthesis of 6(R)-5,6,7,8-tetrahydrobiopterin (BH(4)), a cofactor required for iNOS activity. TNF-alpha also stimulates Sphingosine Kinase, the enzyme that phosphorylates Sphingosine to form Sphingosine-1-phosphate (SPP), a further metabolite of ceramide. Several clones of C6 cells, expressing widely varying levels of Sphingosine Kinase, were used to examine the role of SPP in regulation of GTPCH and BH(4) biosynthesis. Overexpression of Sphingosine Kinase, with concomitant increased endogenous SPP levels, potentiated the effect of TNF-alpha on GTPCH expression and activity and BH(4) biosynthesis. In contrast, enforced expression of Sphingosine Kinase had no effect on iNOS expression or NO formation. Furthermore, N,N-dimethylSphingosine, a potent Sphingosine Kinase inhibitor, completely eliminated the increased GTPCH activity and expression induced by TNF-alpha. Surprisingly, we found that, although C6 cells can secrete SPP, which is enhanced by TNF-alpha, treatment of C6 cells with exogenous SPP or dihydro-SPP had no affect on BH(4) biosynthesis. However, both SPP and dihydro-SPP markedly stimulated ERK 1/2 in C6 cells, which express cell surface SPP receptors. Interestingly, although this ERK activation was blocked by PD98059, which also reduced cellular proliferation induced by enforced expression of Sphingosine Kinase, PD98059 had no effect on GTPCH activity. Collectively, these results suggest that only intracellularly generated SPP plays a role in regulation of GTPCH and BH(4) levels.
Nigel J. Pyne - One of the best experts on this subject based on the ideXlab platform.
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Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors
Trends in pharmacological sciences, 2017Co-Authors: Nigel J. Pyne, David R. Adams, Susan PyneAbstract:The purpose of this Opinion is to present a case for targeting Sphingosine Kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2 −/− mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, Sphingosine Kinase 1 (SK1), which functions as a proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation. Therefore, there is a need to develop highly potent SK2 inhibitors with selectivity over SK1 to clearly define the role of SK2 in autoimmune/inflammatory disease. Structural determinants of SK2 relative to SK1 will enable the design of selective SK2 inhibitors.
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Sphingosine Kinase 2 and multiple myeloma
Oncotarget, 2017Co-Authors: Nigel J. Pyne, Susan PyneAbstract:News on: Sphingosine Kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress, by Wallington-Beddoe et al. Oncotarget. 2017; doi: 10.18632/oncotarget.17115.
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Effect of the Sphingosine Kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension.
Cellular signalling, 2016Co-Authors: Neil Macritchie, Susan Pyne, Giora Volpert, Mohammed Al Washih, David G. Watson, Anthony H. Futerman, Simon Kennedy, Nigel J. PyneAbstract:Recent studies have demonstrated that the expression of Sphingosine Kinase 1, the enzyme that catalyses formation of the bioactive lipid, Sphingosine 1-phosphate, is increased in lungs from patients with pulmonary arterial hypertension. In addition, Sk1−/− mice are protected from hypoxic-induced pulmonary arterial hypertension. Therefore, we assessed the effect of the Sphingosine Kinase 1 selective inhibitor, PF-543 and a Sphingosine Kinase 1/ceramide synthase inhibitor, RB-005 on pulmonary and cardiac remodelling in a mouse hypoxic model of pulmonary arterial hypertension. Administration of the potent Sphingosine Kinase 1 inhibitor, PF-543 in a mouse hypoxic model of pulmonary hypertension had no effect on vascular remodelling but reduced right ventricular hypertrophy. The latter was associated with a significant reduction in cardiomyocyte death. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). In contrast, RB-005 lacked effects on right ventricular hypertrophy, suggesting that Sphingosine Kinase 1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for Sphingosine Kinase 1 in the development of hypertrophy in pulmonary arterial hypertension.
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Crystal Structure of Sphingosine Kinase 1 with Pf-543.
ACS medicinal chemistry letters, 2014Co-Authors: Jing Wang, Susan Pyne, Nigel J. Pyne, Stefan Knapp, Jonathan M. ElkinsAbstract:The most potent inhibitor of Sphingosine Kinase 1 (SPHK1) so far identified is PF-543. The crystal structure of SPHK1 in complex with inhibitor PF-543 to 1.8 A resolution reveals the inhibitor bound in a bent conformation analogous to that expected of a bound Sphingosine substrate but with a rotated head group. The structural data presented will aid in the design of SPHK1 and SPHK2 inhibitors with improved properties.
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Synthesis of Selective Inhibitors of Sphingosine Kinase 1.
ChemInform, 2013Co-Authors: Dong Jae Baek, Susan Pyne, Nigel J. Pyne, Neil Macritchie, Robert BittmanAbstract:Among the novel compounds screened for their inhibitory potency against Sphingosine Kinase 1, derivative (IIIb) exhibits the highest activity.
Susan Pyne - One of the best experts on this subject based on the ideXlab platform.
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Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors
Trends in pharmacological sciences, 2017Co-Authors: Nigel J. Pyne, David R. Adams, Susan PyneAbstract:The purpose of this Opinion is to present a case for targeting Sphingosine Kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2 −/− mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, Sphingosine Kinase 1 (SK1), which functions as a proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation. Therefore, there is a need to develop highly potent SK2 inhibitors with selectivity over SK1 to clearly define the role of SK2 in autoimmune/inflammatory disease. Structural determinants of SK2 relative to SK1 will enable the design of selective SK2 inhibitors.
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Sphingosine Kinase 2 and multiple myeloma
Oncotarget, 2017Co-Authors: Nigel J. Pyne, Susan PyneAbstract:News on: Sphingosine Kinase 2 inhibition synergises with bortezomib to target myeloma by enhancing endoplasmic reticulum stress, by Wallington-Beddoe et al. Oncotarget. 2017; doi: 10.18632/oncotarget.17115.
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Effect of the Sphingosine Kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension.
Cellular signalling, 2016Co-Authors: Neil Macritchie, Susan Pyne, Giora Volpert, Mohammed Al Washih, David G. Watson, Anthony H. Futerman, Simon Kennedy, Nigel J. PyneAbstract:Recent studies have demonstrated that the expression of Sphingosine Kinase 1, the enzyme that catalyses formation of the bioactive lipid, Sphingosine 1-phosphate, is increased in lungs from patients with pulmonary arterial hypertension. In addition, Sk1−/− mice are protected from hypoxic-induced pulmonary arterial hypertension. Therefore, we assessed the effect of the Sphingosine Kinase 1 selective inhibitor, PF-543 and a Sphingosine Kinase 1/ceramide synthase inhibitor, RB-005 on pulmonary and cardiac remodelling in a mouse hypoxic model of pulmonary arterial hypertension. Administration of the potent Sphingosine Kinase 1 inhibitor, PF-543 in a mouse hypoxic model of pulmonary hypertension had no effect on vascular remodelling but reduced right ventricular hypertrophy. The latter was associated with a significant reduction in cardiomyocyte death. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). In contrast, RB-005 lacked effects on right ventricular hypertrophy, suggesting that Sphingosine Kinase 1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for Sphingosine Kinase 1 in the development of hypertrophy in pulmonary arterial hypertension.
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Crystal Structure of Sphingosine Kinase 1 with Pf-543.
ACS medicinal chemistry letters, 2014Co-Authors: Jing Wang, Susan Pyne, Nigel J. Pyne, Stefan Knapp, Jonathan M. ElkinsAbstract:The most potent inhibitor of Sphingosine Kinase 1 (SPHK1) so far identified is PF-543. The crystal structure of SPHK1 in complex with inhibitor PF-543 to 1.8 A resolution reveals the inhibitor bound in a bent conformation analogous to that expected of a bound Sphingosine substrate but with a rotated head group. The structural data presented will aid in the design of SPHK1 and SPHK2 inhibitors with improved properties.
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Synthesis of Selective Inhibitors of Sphingosine Kinase 1.
ChemInform, 2013Co-Authors: Dong Jae Baek, Susan Pyne, Nigel J. Pyne, Neil Macritchie, Robert BittmanAbstract:Among the novel compounds screened for their inhibitory potency against Sphingosine Kinase 1, derivative (IIIb) exhibits the highest activity.
Stuart M Pitson - One of the best experts on this subject based on the ideXlab platform.
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Cigarette smoke inhibits efferocytosis via deregulation of Sphingosine Kinase signaling: reversal with exogenous S1P and the S1P analogue FTY720
Journal of leukocyte biology, 2016Co-Authors: Hai B. Tran, Stuart M Pitson, Jameel Barnawi, Miranda P. Ween, Rhys Hamon, Eugene Roscioli, Greg Hodge, Paul N. Reynolds, Lorena T. Davies, Rainer Viktor HaberbergerAbstract:Alveolar macrophages from chronic obstructive pulmonary disease patients and cigarette smokers are deficient in their ability to phagocytose apoptotic bronchial epithelial cells (efferocytosis). We hypothesized that the defect is mediated via inhibition of Sphingosine Kinases and/or their subcellular mislocalization in response to cigarette smoke and can be normalized with exogenous Sphingosine-1-phosphate or FTY720 (fingolimod), a modulator of Sphingosine-1-phosphate signaling, which has been shown to be clinically useful in multiple sclerosis. Measurement of Sphingosine Kinase 1/2 activities by [(32)P]-labeled Sphingosine-1-phosphate revealed a 30% reduction of Sphingosine Kinase 1 (P < 0.05) and a nonsignificant decrease of Sphingosine Kinase 2 in THP-1 macrophages after 1 h cigarette smoke extract exposure. By confocal analysis macrophage Sphingosine Kinase 1 protein was normally localized to the plasma membrane and cytoplasm and Sphingosine Kinase 2 to the nucleus and cytoplasm but absent at the cell surface. Cigarette smoke extract exposure (24 h) led to a retraction of Sphingosine Kinase 1 from the plasma membrane and Sphingosine Kinase 1/2 clumping in the Golgi domain. Selective inhibition of Sphingosine Kinase 2 with 25 µM ABC294640 led to 36% inhibition of efferocytosis (P < 0.05); 10 µM Sphingosine Kinase inhibitor/5C (Sphingosine Kinase 1-selective inhibitor) induced a nonsignificant inhibition of efferocytosis, but its combination with ABC294640 led to 56% inhibition (P < 0.01 vs. control and < 0.05 vs. single inhibitors). Cigarette smoke-inhibited efferocytosis was significantly (P < 0.05) reversed to near-control levels in the presence of 10-100 nM exogenous Sphingosine-1-phosphate or FTY720, and FTY720 reduced cigarette smoke-induced clumping of Sphingosine Kinase 1/2 in the Golgi domain. These data strongly support a role of Sphingosine Kinase 1/2 in efferocytosis and as novel therapeutic targets in chronic obstructive pulmonary disease.
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Inhibition kinetics and regulation of Sphingosine Kinase 1 expression in prostate cancer cells: functional differences between Sphingosine Kinase 1a and 1b.
The international journal of biochemistry & cell biology, 2012Co-Authors: Keng Gat Lim, Tamara M. Leclercq, Stuart M Pitson, Susan Pyne, Evgeny V. Berdyshev, Francesca Tonelli, Irina Gorshkova, Robert Bittman, Nigel J. PyneAbstract:Sphingosine Kinase 1 catalyses the formation of the bioactive lipid, Sphingosine 1-phosphate and is a target for anti-cancer agents. We demonstrate here that 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi, also referred to as SKI-II), FTY720 (Fingolimod), and (S)-FTY720 vinylphosphonate inhibit Sphingosine Kinase 1 activity with distinct kinetics, indicating that these compounds exhibit different binding modalities with Sphingosine Kinase 1. Thus, SKi is a mixed inhibitor of Sphingosine and ATP binding, whereas FTY720 is competitive with Sphingosine and uncompetitive with ATP, and (S)-FTY720 vinylphosphonate is uncompetitive with Sphingosine and is a mixed inhibitor with respect to ATP. A novel 'see-saw' model is proposed for the binding of inhibitor to catalytic and allosteric sites, the latter dependent on substrate binding, that provides an explanation for the different inhibitor kinetics. In addition, we demonstrate that the expression level and properties unique to an N-terminal 86 amino-acid isoform variant of Sphingosine Kinase 1 (SK1b) in prostate cancer cells reduce its sensitivity to SKi-induced proteasomal degradation in comparison to SK1a, i.e. these two N-terminal variants of Sphingosine Kinase 1 (SK1a and SK1b) have different properties. The reduced sensitivity of SK1b to proteasomal degradation in response to SKi is translated into specific changes in ceramide and S1P levels that leads to apoptosis of androgen-sensitive but not androgen-independent LNCaP prostate cancer cells. Therefore, our proposed 'see-saw' model might be usefully employed in the design of Sphingosine Kinase inhibitors to promote apoptosis of chemotherapeutic resistant cancer cells.
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Over-Expression of Sphingosine Kinase-1 Enhances a Progenitor Phenotype in Human Endothelial Cells
Microcirculation (New York N.Y. : 1994), 2011Co-Authors: Jeffrey M. Barrett, Paul A.b. Moretti, Stuart M Pitson, Kate A. Parham, Jyotsna B. Pippal, Michaelia P. Cockshell, Sarah L. Brice, Claudine S. BonderAbstract:Please cite this paper as: Barrett, Parham, Pippal, Cockshell, Moretti, Brice, Pitson, and Bonder (2011). Over-Expression of Sphingosine Kinase-1 Enhances a Progenitor Phenotype in Human Endothelial Cells. Microcirculation 18(7), 583–597. Abstract Objectives: The use of endothelial progenitor cells in vascular therapies has been limited due to their low numbers present in the bone marrow and peripheral blood. The aim of this study was to investigate the effect of Sphingosine Kinase on the de-differentiation of mature human endothelial cells toward a progenitor phenotype. Methods: The lipid enzyme Sphingosine Kinase-1 was lentivirally over-expressed in human umbilical vein endothelial cells and cells were analyzed for progenitor phenotype and function. Results: Sphingosine Kinase-1 mRNA expression was induced approximately 150-fold with a resultant 20-fold increase in Sphingosine Kinase-1 enzymatic activity. The mRNA expression of the progenitor cell markers CD34, CD133, and CD117 and transcription factor NANOG increased, while the endothelial cell markers analyzed were largely unchanged. The protein level of mature endothelial cell surface markers CD31, CD144, and von Willebrand factor significantly decreased compared to controls. In addition, functional assays provided further evidence for a de-differentiated phenotype with increased viability, reduced uptake of acetylated low-density lipoprotein and decreased tube formation in Matrigel in the cells over-expressing Sphingosine Kinase-1. Conclusions: These findings suggest that over-expression of Sphingosine Kinase-1 in human endothelial cells promotes, in part, their de-differentiation to a progenitor cell phenotype, and is thus a potential tool for the generation of a large population of vascular progenitor cells for therapeutic use.
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Sphingosine Kinase localization in the control of sphingolipid metabolism
Advances in enzyme regulation, 2010Co-Authors: Deanna L. Siow, Stuart M Pitson, Charles D. Anderson, Evgeny V. Berdyshev, Anastasia Skobeleva, Viswanathan Natarajan, Binks W. WattenbergAbstract:The Sphingosine Kinases (Sphingosine Kinase-1 and −2) have been implicated in a variety of physiological functions. Discerning their mechanism of action is complicated because in addition to producing the potent lipid second messenger Sphingosine-1-phoshphate, Sphingosine Kinases, both by producing Sphingosine-1-phosphate and consuming Sphingosine, have profound effects on sphingolipid metabolism. Sphingosine Kinase-1 translocates to the plasma membrane upon agonist stimulation and this translocation is essential for the pro-oncogenic properties of this enzyme. Many of the enzymes of sphingolipid metabolism, including the enzymes that degrade Sphingosine-1-phosphate, are membrane-bound with restricted subcellular distributions. In the work describe here we explore how subcellular localization of Sphingosine Kinase-1 affects the downstream metabolism of Sphingosine-1-phosphate and the access of Sphingosine Kinase to its substrates. We find, surprisingly, that restricting Sphingosine Kinase to either the plasma membrane or the endoplasmic reticulum has a negligible effect on the rate of degradation of the Sphingosine-1-phosphate that is produced. This suggests that Sphingosine-1-phosphate is rapidly transported between membranes. However we also find that cytosolic or endoplasmic-reticulum targeted Sphingosine Kinase expressed at elevated levels produces extremely high levels of dihydroSphingosine-1-phosphate. DihydroSphingosine is a proximal precursor in ceramide biosynthesis. Our data indicate that Sphingosine Kinase can divert substrate from the ceramide de novo synthesis pathway. However plasma membrane-restricted Sphingosine Kinase cannot access the pool of dihydroSphingosine. Therefore whereas Sphingosine Kinase localization does not affect downstream metabolism of Sphingosine-1-phosphate, localization has an important effect on the pools of substrate to which this key signaling enzyme has access.
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Sphingosine Kinase 1 is a critical component of the copper-dependent FGF1 export pathway.
Experimental cell research, 2007Co-Authors: Raffaella Soldi, Stuart M Pitson, Mathew Alexander Vadas, Anna Mandinova, Krishnan Venkataraman, Timoty Hla, Maria F. Duarte, Irene Graziani, Vihren Kolev, Doreen KacerAbstract:Sphingosine Kinase 1 catalyzes the formation of Sphingosine-1-phosphate, a lipid mediator involved in the regulation of angiogenesis. Sphingosine Kinase 1 is constitutively released from cells, even though it lacks a classical signal peptide sequence. Because copper-dependent non-classical stress-induced release of FGF1 also regulates angiogenesis, we questioned whether Sphingosine Kinase 1 is involved in the FGF1 release pathway. We report that (i) the coexpression of Sphingosine Kinase 1 with FGF1 inhibited the release of Sphingosine Kinase 1 at 37 °C; (ii) Sphingosine Kinase 1 was released at 42 °C in complex with FGF1; (iii) Sphingosine Kinase 1 null cells failed to release FGF1 at stress; (iv) Sphingosine Kinase 1 is a high affinity copper-binding protein which formed a complex with FGF1 in a cell-free system, and (v) Sphingosine Kinase 1 over expression rescued the release of FGF1 from inhibition by the copper chelator, tetrathiomolybdate. We propose that Sphingosine Kinase 1 is a component of the copper-dependent FGF1 release pathway.
Olivier Cuvillier - One of the best experts on this subject based on the ideXlab platform.
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Activation of Sphingosine Kinase-1 in cancer: implications for therapeutic targeting.
Current molecular pharmacology, 2010Co-Authors: Olivier Cuvillier, Isabelle Ader, Pierre Bouquerel, Leyre Brizuela, Bernard Malavaud, Catherine Mazerolles, Pascal RischmannAbstract:Sphingolipid metabolites are critical to the regulation of a number of fundamental biological processes including cancer. Whereas ceramide and Sphingosine mediate and trigger apoptosis or cell growth arrest, Sphingosine 1-phosphate promotes proliferation, cell survival and angiogenesis. The delicate equilibrium between the intracellular levels of each of these sphingolipids is controlled by the enzymes that either produce or degrade these metabolites. Sphingosine Kinase-1 is a crucial regulator of this two-pan balance, because its produces the pro-survival and pro-angiogenic Sphingosine 1-phosphate and decreases the amount of both ceramide and Sphingosine, the pro-apoptotic sphingolipids. Moreover, its gene is oncogenic, its mRNA is overproduced in several solid tumors, its overexpression protects cells from apoptosis, and its activity is down-regulated by anti-cancer treatments. Therefore, the Sphingosine Kinase-1/Sphingosine 1-phosphate signaling pathway appears to be a target of interest for therapeutic manipulation.
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Downregulating Sphingosine Kinase-1 for cancer therapy
Expert opinion on therapeutic targets, 2008Co-Authors: Olivier CuvillierAbstract:Background: The sphingolipids ceramide and Sphingosine 1-phosphate (S1P) are key regulators of cell death and proliferation. The subtle balance between their intracellular levels is governed mainly by Sphingosine Kinase-1, which produces the pro-survival S1P. Sphingosine Kinase-1 is an oncogene; is overexpressed in many tumors; protects cancer cells from apoptosis in vitro and in vivo; and its activity is decreased by anticancer therapies. Hence, Sphingosine Kinase-1 appears to be a target of interest for therapeutic manipulation. Objective: This review considers recent developments regarding the involvement of Sphingosine Kinase-1 as a therapeutic target for cancer, and describes the pharmacological tools currently available. Results/conclusion: The studies described provide strong evidence that strategies to kill cancer cells via Sphingosine Kinase-1 inhibition are valid and could have a favorable therapeutic index.
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Sphingosine Kinase-1--a potential therapeutic target in cancer.
Anti-cancer drugs, 2007Co-Authors: Olivier CuvillierAbstract:Sphingolipid metabolites play critical functions in the regulation of a number of fundamental biological processes including cancer. Whereas ceramide and Sphingosine mediate and trigger apoptosis or cell growth arrest, Sphingosine 1-phosphate promotes proliferation and cell survival. The delicate equilibrium between the intracellular levels of each of these sphingolipids is controlled by the enzymes that either produce or degrade these metabolites. Sphingosine Kinase-1 is a crucial regulator of this two-pan balance, because it produces the prosurvival Sphingosine 1-phosphate, and reduces the content of both ceramide and Sphingosine, the proapoptotic sphingolipids. Sphingosine Kinase-1 controls the levels of sphingolipids having opposite effects on cell survival/death, its gene was found to be of oncogenic nature, its mRNA is overexpressed in many solid tumors, its overexpression protects cells from apoptosis and its activity is decreased during anticancer treatments. Therefore, Sphingosine Kinase-1 appears to be a target of interest for therapeutic manipulation via its pharmacological inhibition. Strategies to kill tumor cells by increasing their ceramide and/or Sphingosine content while blocking Sphingosine 1-phosphate generation should have a favorable therapeutic index.
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Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting Sphingosine Kinase-1.
Leukemia, 2005Co-Authors: Elisabeth Bonhoure, Dimitri Pchejetski, Nassera Aouali, Hamid Morjani, Thierry Levade, T Kohama, Olivier CuvillierAbstract:We examined the involvement of Sphingosine Kinase-1, a critical regulator of the sphingolipid balance, in susceptibility to antineoplastic agents of either sensitive or multidrug-resistant acute myeloid leukemia cells. Contrary to parental HL-60 cells, doxorubicin and etoposide failed to trigger apoptosis in chemoresistant HL-60/Doxo and HL-60NP16 cells overexpressing MRP1 and MDR1, respectively. Chemosensitive HL-60 cells displayed Sphingosine Kinase-1 inhibition coupled with ceramide generation. In contrast, chemoresistant HL-60/ Doxo and HL-60/VP16 had sustained Sphingosine Kinase-1 activity and did not produce ceramide during treatment. Enforced expression of Sphingosine Kinase-1 in chemosensitive HL-60 cells resulted in marked inhibition of apoptosis that was mediated by blockade of mitochondrial cytochrome c efflux hence suggesting a control of apoptosis at the pre-mitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a Sphingosine Kinase-1 inhibition and apoptosis both prevented by Sphingosine Kinase-1 over-expression. Furthermore, F-12509a, a new Sphingosine Kinase inhibitor, led to ceramide accumulation, decrease in Sphingosine 1-phosphate content and caused apoptosis equally in chemosensitive and chemoresistant cell lines that is inhibited by adding Sphingosine 1-phosphate or overexpressing Sphingosine Kinase-1. F-12509a induced classical apoptosis hallmarks namely nuclear fragmentation, caspase-3 cleavage as well as downregulation of antiapoptotic XIAP, and release of cytochrome c and SMAC/Diablo.
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Sphingosine Kinase Expression Increases Intracellular Sphingosine-1-Phosphate and Promotes Cell Growth and Survival
The Journal of cell biology, 1999Co-Authors: Ana Olivera, Samantha Poulton, Lisa C Edsall, Olivier Cuvillier, Victor E. Nava, Takafumi Kohama, Sarah SpiegelAbstract:Sphingosine-1-phosphate (SPP) is a bioactive lipid that has recently been identified as the ligand for the EDG family of G protein–coupled cell surface receptors. However, the mitogenic and survival effects of exogenous SPP may not correlate with binding to cell-surface receptors (Van Brocklyn, J.R., M.J. Lee, R. Menzeleev, A. Olivera, L. Edsall, O. Cuvillier, D.M. Thomas, P.J.P. Coopman, S. Thangada, T. Hla, and S. Spiegel. 1998. J. Cell Biol. 142:229–240). The recent cloning of Sphingosine Kinase, a unique lipid Kinase responsible for the formation of SPP, has provided a new tool to investigate the role of intracellular SPP. Expression of Sphingosine Kinase markedly increased SPP levels in NIH 3T3 fibroblasts and HEK293 cells, but no detectable secretion of SPP into the medium was observed. The increased Sphingosine Kinase activity in NIH 3T3 fibroblasts was sufficient to promote growth in low- serum media, expedite the G1/S transition, and increase DNA synthesis and the proportion of cells in the S phase of the cell cycle with a concomitant increase in cell numbers. Transient or stable overexpression of Sphingosine Kinase in NIH 3T3 fibroblasts or HEK293 cells protected against apoptosis induced by serum deprivation or ceramide elevation. N,N-DimethylSphingosine, a competitive inhibitor of Sphingosine Kinase, blocked the effects of Sphingosine Kinase overexpression on cell proliferation and suppression of apoptosis. In contrast, pertussis toxin did not abrogate these biological responses. In Jurkat T cells, overexpression of Sphingosine Kinase also suppressed serum deprivation- and ceramide-induced apoptosis and, to a lesser extent, Fas-induced apoptosis, which correlated with inhibition of DEVDase activity, as well as inhibition of the executionary caspase-3. Taken together with ample evidence showing that growth and survival factors activate Sphingosine Kinase, our results indicate that SPP functions as a second messenger important for growth and survival of cells. Hence, SPP belongs to a novel class of lipid mediators that can function inside and outside cells.