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Stuart M Pitson - One of the best experts on this subject based on the ideXlab platform.
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Sphingosine Kinase 1 in viral infections.
Reviews in medical virology, 2012Co-Authors: Jillian M. Carr, Claudine S. Bonder, Suresh Mahalingam, Stuart M PitsonAbstract:Sphingosine Kinase 1 (SphK1) is an enzyme that phosphorylates the lipid Sphingosine to generate Sphingosine-1-phosphate (S1P). S1P can act intracellularly as a signaling molecule and extracellularly as a receptor ligand. The SphK1/S1P axis has well-described roles in cell signaling, the cell death/survival decision, the production of a pro-inflammatory response, immunomodulation, and control of vascular integrity. Agents targeting the SphK1/S1P axis are being actively developed as therapeutics for cancer and immunological and inflammatory disorders. Control of cell death/survival and pro-inflammatory immune responses is central to the pathology of infectious disease, and we can capitalize on the knowledge provided by investigations of SphK1/S1P in cancer and immunology to assess its application to selected human infections. We have herein reviewed the growing literature relating viral infections to changes in SphK1 and S1P. SphK1 activity is reportedly increased following human cytomegalovirus and respiratory syncytial virus infections, and elevated SphK1 enhances influenza virus infection. In contrast, SphK1 activity is reduced in bovine viral diarrhea virus and dengue virus infections. Sphingosine analogs that modulate S1P receptors have proven useful in animal models in alleviating influenza virus infection but have shown no benefit in simian human immunodeficiency virus and lymphocytic choriomeningitis virus infections. We have rationalized a role for SphK1/S1P in dengue virus, chikungunya virus, and Ross River virus infections, on the basis of the biology and the pathology of these diseases. The increasing number of effective SphK1 and S1P modulating agents currently in development makes it timely to investigate these roles with the potential for developing modulators of SphK1 and S1P for novel anti-viral therapies.
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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, Evgeny V. Berdyshev, Francesca Tonelli, Irina Gorshkova, Robert BittmanAbstract: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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the Sphingosine Kinase 1 inhibitor 2 p hydroxyanilino 4 p chlorophenyl thiazole induces proteasomal degradation of Sphingosine Kinase 1 in mammalian cells
Journal of Biological Chemistry, 2010Co-Authors: Carolyn Loveridge, Tamara M. Leclercq, Stuart M Pitson, Keng Gat Lim, Evgeny V. Berdyshev, Francesca Tonelli, Jaclyn S Long, Rothwelle J Tate, Viswanathan Natarajan, Nigel J PyneAbstract:Sphingosine Kinase 1 (SK1) is an enzyme that catalyzes the phosphorylation of Sphingosine to produce the bioactive lipid Sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome. In addition, the proteasomal degradation of SK1a and SK1b in androgen-sensitive LNCaP cells is associated with the induction of apoptosis. However, SK1b in LNCaP-AI cells (androgen-independent) is less sensitive to SKi-induced proteasomal degradation and these cells are resistant to SKi-induced apoptosis, thereby implicating the ubiquitin-proteasomal degradation of SK1 as an important mechanism controlling cell survival.
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Sphingosine Kinase 1 activity and expression in human prostate cancer resection specimens
European Journal of Cancer, 2010Co-Authors: Bernard Malavaud, Stuart M Pitson, Dimitri Pchejetski, Catherine Mazerolles, Pascal Rischmann, Geisilene Silva Russano De Paiva, Cyril Calvet, N Doumerc, Olivier CuvillierAbstract:Abstract Purpose Sphingosine Kinase-1 (SphK1) was shown in preclinical models and non-genitourinary cancers to be instrumental in cancer progression, adaptation to hypoxia and in tumour angiogenesis. No data were available in human prostate cancer. The present study was designed to assess SphK1 expression and activity in radical prostatectomy specimens and to research correlations with clinical features. Materials and methods Transverse section of fresh tissue was obtained from 30 consecutive patients undergoing laparoscopic prostatectomy. SphK1 enzymatic activities of tumour and normal counterpart were determined. Relationships with PSA, Gleason sum, pathological stage, resection margin status and treatment failure were researched. SphK1 pattern of expression was then assessed on tissue microarray. Results A significant 2-fold increase in SphK1 enzymatic activity(11.1 ± 8.4 versus 5.9 ± 3.2 (P Conclusion In complement to preclinical literature, the demonstrated relationships between SphK1-increased activity in cancer and relevant clinical features confirm a central role for SphK1 in prostate cancer that herald promising avenues in risk-assessment and treatment.
Nigel J Pyne - One of the best experts on this subject based on the ideXlab platform.
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Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?
Trends in molecular medicine, 2017Co-Authors: Nigel J Pyne, Susan PyneAbstract:Sphingosine Kinase 1 (SphK1) knockout mice are protected against pulmonary hypertension and expression levels of the enzyme are increased in the lungs of pulmonary arterial hypertensive (PAH) patients. Moreover, Sphingosine 1-phosphate can promote vascular remodeling/vasoconstriction in rodent and human pulmonary arterial smooth muscle cell models. Therefore, SphK1 might be a novel target for treatment of PAH. However, in our opinion, more refined strategies to target SphK1 are needed because this enzyme is protective against endothelial dysfunction and can become resistant to SphK1 inhibitors in vascular smooth muscle, thereby potentially limiting their effectiveness in PAH. In addition, SphK1 is involved in maladaptive hypertrophy and we propose that heart failure might be an additional direct target for therapeutic intervention with SphK1 inhibitors.
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Sphingosine 1-phosphate receptors and Sphingosine Kinase 1: novel biomarkers for clinical prognosis in breast, prostate, and hematological cancers
Frontiers in oncology, 2012Co-Authors: Susan Pyne, Joanne Edwards, Jan Ohotski, Nigel J PyneAbstract:There is substantial evidence for a role in cancer of the bioactive lipid Sphingosine 1-phosphate (S1P), the enzyme Sphingosine Kinase 1 (that catalyses S1P formation) and S1P-specific G protein-coupled receptors. This perspective highlights recent findings demonstrating that Sphingosine Kinase 1 and S1P receptors are new important biomarkers for detection of early cancer and progression to aggressive cancer. The impact of the sub-cellular distribution of S1P metabolizing enzymes and S1P receptors and their spatial functional interaction with oncogenes is considered with respect to prognostic outcome. These findings suggest that S1P, in addition to being a biomarker of clinical prognosis, might also be a new therapeutic target for intervention in cancer.
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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
International journal of cancer, 2012Co-Authors: Jan Ohotski, Susan Pyne, Joanne Edwards, B. Elsberger, Carol Watson, Clare Orange, Elizabeth Mallon, Nigel J PyneAbstract:Sphingosine Kinase is an enzyme that catalyses the phosphorylation of Sphingosine to form Sphingosine 1-phosphate. Sphingosine 1-phosphate is a bioactive lipid, which has been shown to have an important role in promoting the survival, growth and invasiveness of cancer cells. Sphingosine 1-phosphate binds to five different plasma membrane Sphingosine 1-phosphate receptors (S1P1–5) and can regulate intracellular target proteins. We have used immunohistochemical analysis to determine the concurrent expression levels of Sphingosine Kinase 1 or S1P receptors and other signaling proteins in estrogen receptor-positive breast cancer tumors and have then assessed the impact of these combinations on clinical outcome. This approach has enabled identification of (i) novel biomarkers and (ii) several spatially controlled associations between either Sphingosine Kinase 1 or S1P1–3 and other signaling proteins whose combination affect prognosis. For instance, the translocation of Sphingosine Kinase 1 to the plasma membrane has been shown to be a critical determinant in cancer progression. However, our findings identify an additional novel role for the nuclear localization of Sphingosine Kinase 1 combined with either ERK-1/2 or SFK or LYN or AKT or NF-κB, which significantly shortens disease-specific survival and/or recurrence. We also demonstrate that nuclear S1P2 receptor and c-SRC are associated with improved prognosis and this is linked with a reduction in the nuclear localization of Sphingosine Kinase 1. These findings identify potential novel biomarker associations, which might serve as new targets for drug intervention designed to improve treatment of estrogen receptor-positive breast cancer.
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Resveratrol dimers are novel Sphingosine Kinase 1 inhibitors and affect Sphingosine Kinase 1 expression and cancer cell growth and survival
British journal of pharmacology, 2012Co-Authors: Keng Gat Lim, Susan Pyne, Alexander I. Gray, Nigel J PyneAbstract:Sphingosine Kinase 1 catalyses formation of the bioactive lipid, Sphingosine 1-phosphate, which protects cancer cells from apoptosis. Therefore, Sphingosine Kinase 1 is a novel target for intervention with anti-cancer agents. We have assessed the effect of the anti-cancer agent, resveratrol and its dimers (ampelopsin A and balanocarpol) on Sphingosine Kinase 1 activity and on survival of MCF-7 breast cancer cells. Ampelopsin A and balanocarpol were purified from Hopea dryobalanoides and their effect on Sphingosine Kinase 1 activity and expression, [3H] thymidine incorporation, ERK-1/2 phosphorylation and PARP activity assessed in MCF-7 cells. Resveratrol, ampelopsin A and balanocarpol were novel inhibitors of Sphingosine Kinase 1 activity. Balanocarpol was a mixed inhibitor (with Sphingosine) of Sphingosine Kinase 1 with a Kic= 90 +/- 10 mu M and a Kiu of similar to 500 mu M. Balanocarpol and ampelopsin A also induced down-regulation of Sphingosine Kinase 1 expression and reduced DNA synthesis, while balanocarpol stimulated PARP cleavage in MCF-7 breast cancer cells. Resveratrol was a competitive inhibitor (with Sphingosine) of Sphingosine Kinase 1 with a Kic= 160 +/- 40 mu M, reduced Sphingosine Kinase 1 expression and induced PARP cleavage in MCF-7 cells. Each molecule of balanocarpol may bind at least two Sphingosine Kinase 1 catalytic molecules to reduce the activity of each simultaneously. These findings suggest that resveratrol, ampelopsin A and balanocarpol could perturb Sphingosine Kinase 1-mediated signalling and this might explain their activity against MCF-7 breast cancer cells. This article is commented on by Hergst and Yun, pp. 16031604 of this issue. To view this commentary visit
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the Sphingosine Kinase 1 inhibitor 2 p hydroxyanilino 4 p chlorophenyl thiazole induces proteasomal degradation of Sphingosine Kinase 1 in mammalian cells
Journal of Biological Chemistry, 2010Co-Authors: Carolyn Loveridge, Tamara M. Leclercq, Stuart M Pitson, Keng Gat Lim, Evgeny V. Berdyshev, Francesca Tonelli, Jaclyn S Long, Rothwelle J Tate, Viswanathan Natarajan, Nigel J PyneAbstract:Sphingosine Kinase 1 (SK1) is an enzyme that catalyzes the phosphorylation of Sphingosine to produce the bioactive lipid Sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome. In addition, the proteasomal degradation of SK1a and SK1b in androgen-sensitive LNCaP cells is associated with the induction of apoptosis. However, SK1b in LNCaP-AI cells (androgen-independent) is less sensitive to SKi-induced proteasomal degradation and these cells are resistant to SKi-induced apoptosis, thereby implicating the ubiquitin-proteasomal degradation of SK1 as an important mechanism controlling cell survival.
Olivier Cuvillier - One of the best experts on this subject based on the ideXlab platform.
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Biochemical methods for quantifying sphingolipids: ceramide, Sphingosine, Sphingosine Kinase-1 activity, and Sphingosine-1-phosphate.
Methods in molecular biology (Clifton N.J.), 2012Co-Authors: Leyre Brizuela, Olivier CuvillierAbstract:Sphingolipids (ceramide, Sphingosine, and Sphingosine-1-phosphate) are bioactive lipids with important biological functions in proliferation, apoptosis, angiogenesis, and inflammation. Herein, we describe easy and rapid biochemical methods with the use of radiolabeled molecules ((3)H, (32)P) for their mass determination. Quantitation of Sphingosine Kinase-1 activity, the most studied isoform, is also included.
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Sphingosine Kinase 1 activity and expression in human prostate cancer resection specimens
European Journal of Cancer, 2010Co-Authors: Bernard Malavaud, Stuart M Pitson, Dimitri Pchejetski, Catherine Mazerolles, Pascal Rischmann, Geisilene Silva Russano De Paiva, Cyril Calvet, N Doumerc, Olivier CuvillierAbstract:Abstract Purpose Sphingosine Kinase-1 (SphK1) was shown in preclinical models and non-genitourinary cancers to be instrumental in cancer progression, adaptation to hypoxia and in tumour angiogenesis. No data were available in human prostate cancer. The present study was designed to assess SphK1 expression and activity in radical prostatectomy specimens and to research correlations with clinical features. Materials and methods Transverse section of fresh tissue was obtained from 30 consecutive patients undergoing laparoscopic prostatectomy. SphK1 enzymatic activities of tumour and normal counterpart were determined. Relationships with PSA, Gleason sum, pathological stage, resection margin status and treatment failure were researched. SphK1 pattern of expression was then assessed on tissue microarray. Results A significant 2-fold increase in SphK1 enzymatic activity(11.1 ± 8.4 versus 5.9 ± 3.2 (P Conclusion In complement to preclinical literature, the demonstrated relationships between SphK1-increased activity in cancer and relevant clinical features confirm a central role for SphK1 in prostate cancer that herald promising avenues in risk-assessment and treatment.
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Sphingosine Kinase 1 inhibition sensitizes hormone-resistant prostate cancer to docetaxel.
International journal of cancer, 2009Co-Authors: Lysann Sauer, Olivier Cuvillier, Joao Nunes, Jonathan Waxman, Vishal Salunkhe, Lenka Skalska, Takafumi Kohama, D. PchejetskiAbstract:It has recently been shown that docetaxel chemotherapy is effective in prolonging life in patients with prostate cancer (PCa). We have investigated potential ways of increasing the effectiveness of chemotherapy in this disease. We have previously reported that Sphingosine Kinase 1 (SphK1) inhibition is a key step in docetaxel-induced apoptosis in the PC-3 PCa cell line and that pharmacologicalSphK1 inhibition is chemosensitizing in the docetaxel-resistant PCa LNCaP cell line. In this study we have addressed the mechanism of docetaxel-induced apoptosis of PC-3 cells and identified SphK1-dependent and -independent components. We have shown that SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Using hormoneresistant PC-3 and DU145 PCa cells we have demonstrated that both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose. This work points out to potential ways of increasing the effectiveness of chemotherapy for PCa by SphK1 inhibition.
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Sphingosine Kinase-1 mediates androgen-induced osteoblast cell growth.
Biochemical and biophysical research communications, 2009Co-Authors: Claire Martin, Bernard Malavaud, Jean-michel Lafosse, Olivier CuvillierAbstract:Herein we report that the lipid Kinase Sphingosine Kinase-1 (SphK1) is instrumental in mediating androgen-induced cell proliferation in osteoblasts. Dihydrotestosterone (DHT) triggered cell growth in steroid-deprived MC3T3 cells, which was associated with a rapid stimulation of SphK1 and activation of both Akt and ERK signaling pathways. This mechanism relied on functional androgen receptor/PI3K/Akt nongenotropic signaling as pharmacological antagonists could block SphK1 stimulation by DHT and its consequences. Finally, SphK1 inhibition not only abrogated DHT-induced ERK activation but also blocked cell proliferation, while ERK inhibition had no impact, suggesting that SphK1 was critical for DHT signaling yet independently of the ERK.
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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.
Susan Pyne - One of the best experts on this subject based on the ideXlab platform.
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Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?
Trends in molecular medicine, 2017Co-Authors: Nigel J Pyne, Susan PyneAbstract:Sphingosine Kinase 1 (SphK1) knockout mice are protected against pulmonary hypertension and expression levels of the enzyme are increased in the lungs of pulmonary arterial hypertensive (PAH) patients. Moreover, Sphingosine 1-phosphate can promote vascular remodeling/vasoconstriction in rodent and human pulmonary arterial smooth muscle cell models. Therefore, SphK1 might be a novel target for treatment of PAH. However, in our opinion, more refined strategies to target SphK1 are needed because this enzyme is protective against endothelial dysfunction and can become resistant to SphK1 inhibitors in vascular smooth muscle, thereby potentially limiting their effectiveness in PAH. In addition, SphK1 is involved in maladaptive hypertrophy and we propose that heart failure might be an additional direct target for therapeutic intervention with SphK1 inhibitors.
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Sphingosine 1-phosphate receptors and Sphingosine Kinase 1: novel biomarkers for clinical prognosis in breast, prostate, and hematological cancers
Frontiers in oncology, 2012Co-Authors: Susan Pyne, Joanne Edwards, Jan Ohotski, Nigel J PyneAbstract:There is substantial evidence for a role in cancer of the bioactive lipid Sphingosine 1-phosphate (S1P), the enzyme Sphingosine Kinase 1 (that catalyses S1P formation) and S1P-specific G protein-coupled receptors. This perspective highlights recent findings demonstrating that Sphingosine Kinase 1 and S1P receptors are new important biomarkers for detection of early cancer and progression to aggressive cancer. The impact of the sub-cellular distribution of S1P metabolizing enzymes and S1P receptors and their spatial functional interaction with oncogenes is considered with respect to prognostic outcome. These findings suggest that S1P, in addition to being a biomarker of clinical prognosis, might also be a new therapeutic target for intervention in cancer.
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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
International journal of cancer, 2012Co-Authors: Jan Ohotski, Susan Pyne, Joanne Edwards, B. Elsberger, Carol Watson, Clare Orange, Elizabeth Mallon, Nigel J PyneAbstract:Sphingosine Kinase is an enzyme that catalyses the phosphorylation of Sphingosine to form Sphingosine 1-phosphate. Sphingosine 1-phosphate is a bioactive lipid, which has been shown to have an important role in promoting the survival, growth and invasiveness of cancer cells. Sphingosine 1-phosphate binds to five different plasma membrane Sphingosine 1-phosphate receptors (S1P1–5) and can regulate intracellular target proteins. We have used immunohistochemical analysis to determine the concurrent expression levels of Sphingosine Kinase 1 or S1P receptors and other signaling proteins in estrogen receptor-positive breast cancer tumors and have then assessed the impact of these combinations on clinical outcome. This approach has enabled identification of (i) novel biomarkers and (ii) several spatially controlled associations between either Sphingosine Kinase 1 or S1P1–3 and other signaling proteins whose combination affect prognosis. For instance, the translocation of Sphingosine Kinase 1 to the plasma membrane has been shown to be a critical determinant in cancer progression. However, our findings identify an additional novel role for the nuclear localization of Sphingosine Kinase 1 combined with either ERK-1/2 or SFK or LYN or AKT or NF-κB, which significantly shortens disease-specific survival and/or recurrence. We also demonstrate that nuclear S1P2 receptor and c-SRC are associated with improved prognosis and this is linked with a reduction in the nuclear localization of Sphingosine Kinase 1. These findings identify potential novel biomarker associations, which might serve as new targets for drug intervention designed to improve treatment of estrogen receptor-positive breast cancer.
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Resveratrol dimers are novel Sphingosine Kinase 1 inhibitors and affect Sphingosine Kinase 1 expression and cancer cell growth and survival
British journal of pharmacology, 2012Co-Authors: Keng Gat Lim, Susan Pyne, Alexander I. Gray, Nigel J PyneAbstract:Sphingosine Kinase 1 catalyses formation of the bioactive lipid, Sphingosine 1-phosphate, which protects cancer cells from apoptosis. Therefore, Sphingosine Kinase 1 is a novel target for intervention with anti-cancer agents. We have assessed the effect of the anti-cancer agent, resveratrol and its dimers (ampelopsin A and balanocarpol) on Sphingosine Kinase 1 activity and on survival of MCF-7 breast cancer cells. Ampelopsin A and balanocarpol were purified from Hopea dryobalanoides and their effect on Sphingosine Kinase 1 activity and expression, [3H] thymidine incorporation, ERK-1/2 phosphorylation and PARP activity assessed in MCF-7 cells. Resveratrol, ampelopsin A and balanocarpol were novel inhibitors of Sphingosine Kinase 1 activity. Balanocarpol was a mixed inhibitor (with Sphingosine) of Sphingosine Kinase 1 with a Kic= 90 +/- 10 mu M and a Kiu of similar to 500 mu M. Balanocarpol and ampelopsin A also induced down-regulation of Sphingosine Kinase 1 expression and reduced DNA synthesis, while balanocarpol stimulated PARP cleavage in MCF-7 breast cancer cells. Resveratrol was a competitive inhibitor (with Sphingosine) of Sphingosine Kinase 1 with a Kic= 160 +/- 40 mu M, reduced Sphingosine Kinase 1 expression and induced PARP cleavage in MCF-7 cells. Each molecule of balanocarpol may bind at least two Sphingosine Kinase 1 catalytic molecules to reduce the activity of each simultaneously. These findings suggest that resveratrol, ampelopsin A and balanocarpol could perturb Sphingosine Kinase 1-mediated signalling and this might explain their activity against MCF-7 breast cancer cells. This article is commented on by Hergst and Yun, pp. 16031604 of this issue. To view this commentary visit
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Sphingosine Kinase 1 is an intracellular effector of phosphatidic acid
Journal of Biological Chemistry, 2004Co-Authors: C Delon, Susan Pyne, Maria Manifava, Eleanor Wood, Dawn Thompson, Sonja Krugmann, Nicholas T KtistakisAbstract:Sphingosine Kinase 1 (SK1) phosphorylates Sphingosine to generate Sphingosine 1-phosphate (S1P). Because both substrate and product of the enzyme are potentially important signaling molecules, the regulation of SK1 is of considerable interest. We report that SK1, which is ordinarily a cytosolic enzyme, translocates in vivo and in vitro to membrane compartments enriched in phosphatidic acid (PA), the lipid product of phospholipase D. This translocation depends on direct interaction of SK1 with PA, because recombinant purified enzyme shows strong affinity for pure PA coupled to Affi-Gel. The SK1-PA interaction maps to the C terminus of SK1 and is independent of catalytic activity or of the diacylglycerol Kinase-like domain of the enzyme. Thus SK1 constitutes a novel, physiologically relevant PA effector.
Lina M Obeid - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional Regulation of Sphingosine Kinase 1.
Cells, 2020Co-Authors: Joseph Bonica, Lina M Obeid, Cungui Mao, Yusuf A HannunAbstract: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.
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Molecular mechanisms of regulation of Sphingosine Kinase 1.
Biochimica et biophysica acta. Molecular and cell biology of lipids, 2018Co-Authors: Michael J. Pulkoski-gross, Lina M ObeidAbstract:Abstract Within the last 3 decades, there has been intense study of bioactive sphingolipids and the enzymes which metabolize those lipids. One enzyme is the critical lipid Kinase Sphingosine Kinase 1 (SK1), which produces the potent and pleiotropic signaling lipid, Sphingosine 1-phosphate (S1P). SK1 and S1P have been implicated in a host of different diseases including cancer, chronic inflammation, and metabolic diseases. However, while there is ample knowledge about the importance of these molecules in the development and progression of disease there is a dearth of knowledge of the molecular mechanisms which regulate SK1 function. In this review, we will cover some of the more recent and exciting findings about the different ways SK1 function can be regulated, from transcriptional regulation to protein stability. Finally, we will delve into recent structural insights into SK1 and how they might relate to function at cell membranes.
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A novel role of Sphingosine Kinase-1 in the invasion and angiogenesis of VHL mutant clear cell renal cell carcinoma
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015Co-Authors: Mohamed Salama, Yusuf A Hannun, Michael J. Pulkoski-gross, Brittany Carroll, Mohamad Adada, Lina M ObeidAbstract:Sphingosine Kinase 1 (SK1), the enzyme responsible for Sphingosine 1-phosphate (S1P) production, is overexpressed in many human solid tumors. However, its role in clear cell renal cell carcinoma (c...
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Effect of Sphingosine Kinase 1 inhibition on blood pressure
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2012Co-Authors: Hideki Furuya, Lina M Obeid, Yusuf A Hannun, Yoshiko Shimizu, Masayuki Wada, Paulette M. Yamada, Toshihiko KawamoriAbstract:Accumulating evidence suggests that Sphingosine Kinase 1 (SphK1) plays a key role in carcinogenesis by regulating cyclooxygenase-2 (COX-2) expression. Recent clinical studies have revealed that COX-2 inhibitors cause adverse cardiovascular side effects, likely due to inhibition of prostacyclin (PGI(2)). In this work, we investigated the roles of SphK1 inhibition on blood pressure (BP). The results show that lack of SphK1 expression did not exacerbate angiotensin II (Ang II)-induced acute hypertension, whereas celecoxib, a COX-2 inhibitor, augmented and sustained higher BP in mice. Interestingly, SphK1-knockout mice inhibited prostaglandin E(2) (PGE(2)) but not PGI(2) production in response to Ang II, whereas celecoxib blocked both PGE(2) and PGI(2) production. Mechanistically, SphK1 down-regulation by siRNA in human umbilical vein endothelial cells decreased cytokine-induced PGE(2) production primarily through inhibition of microsomal PGE synthase-1 (mPGES-1), not COX-2. SphK1 down-regulation also decreased MKK6 expression, which phosphorylates and activates P38 MAPK, which, in turn, regulates early growth response-1 (Egr-1), a transcription factor of mPGES-1. Together, these data indicate that SphK1 regulates PGE(2) production by mPGES-1 expression via the p38 MAPK pathway, independent of COX-2 signaling, in endothelial cells, suggesting that SphK1 inhibition may be a promising strategy for cancer chemoprevention with lack of the adverse cardiovascular side effects associated with coxibs.
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Role of Sphingosine Kinase-1 in paracrine/transcellular angiogenesis and lymphangiogenesis in vitro.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2010Co-Authors: Viviana Anelli, Christopher R. Gault, Ashley J. Snider, Lina M ObeidAbstract:Sphingosine-1-phosphate (S1P) is an important bioactive sphingolipid involved in angiogenesis and lymphangiogenesis, 2 important processes that influence the growth, survival, and spread of tumors. S1P acts as an extracellular mediator through binding to 5 highly specific S1P receptors, S1P1–5. Sphingosine Kinase-1 (SK1), one of 2 known Sphingosine Kinase enzymes responsible for S1P production, appears to be overexpressed in many tumors. Although a role for S1P in angiogenesis and lymphangiogenesis has been established, it is unclear whether S1P secreted from cancer cells has a paracrine function in a tumor environment. Here we investigated whether modulation of cellular SK1 could initiate a paracrine angiogenic and lymphangiogenic switch. We found that SK1 overexpression in HEK cells or its down-regulation in glioma or breast cancer cells modulated extracellular S1P levels accordingly, which in turn increased or decreased both migration and tube formation in cocultured vascular or lymphatic endothelial cells. In contrast, down-regulation of Sphingosine Kinase 2 in both glioma and breast cancer cells had no appreciable effect on cellular or secreted S1P levels. In addition, vascular endothelial growth factors VEGF and VEGF-C down-regulation in cancer cells appeared insufficient to block the angiogenic and lymphangiogenic switch triggered by these cells. Moreover, S1P initiated endothelial cell sprouting in 3-dimensional collagen matrices, which is representative of a multistep angiogenic process. Our data collectively demonstrate for the first time that SK1 plays an essential role in regulating in vitro paracrine angiogenesis and lymphangiogenesis.—Anelli, V., Gault, C. R., Snider, A. J., Obeid, L. M. Role of Sphingosine Kinase-1 in paracrine/transcellular angiogenesis and lymphangiogenesis in vitro.