scholarly journals Sphingosine kinase localization in the control of sphingolipid metabolism

2011 ◽  
Vol 51 (1) ◽  
pp. 229-244 ◽  
Author(s):  
Deanna L. Siow ◽  
Charles D. Anderson ◽  
Evgeny V. Berdyshev ◽  
Anastasia Skobeleva ◽  
Viswanathan Natarajan ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Sphingolipid Metabolism

scholarly journals K27Q/K29Q mutations in sphingosine kinase 1 attenuate high-fat diet induced obesity and altered glucose homeostasis in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jing Xie ◽  
Yong Shao ◽  
Jin Liu ◽  
Meilan Cui ◽  
Xiuxiao Xiao ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Metabolic Diseases ◽  
Sphingosine Kinase ◽  
Protective Role ◽  
Sphingolipid Metabolism ◽  
Acid Oxidation ◽  
Sphingosine Kinase 1 ◽  
High Fat ◽  
Triglyceride Accumulation ◽  
Altered Glucose

AbstractObesity and its associated metabolic disorders are increasingly impacting public health worldwide. Sphingosine kinase 1 (Sphk1) is a critical enzyme in sphingolipid metabolism that has been implicated in various metabolic syndromes. In this study, we developed a mouse model constitutively expressing pseudoacetylated mouse Sphk1 (QSPHK1) to study its role in regulating glucose and lipid metabolism. The results showed that QSPHK1 mice gained less body weight than wide type (WT) mice on a high-fat diet, and QSPHK1 mice had improved glucolipid metabolism and insulin. Moreover, QSPHK1 mice had alleviated hepatic triglyceride accumulation and had high-fat-diet-induced hepatic steatosis that occurred as a result of reduced lipogenesis and enhanced fatty acid oxidation, which were mediated by the AMPK/ACC axis and the FGF21/adiponectin axis. Collectively, this study provided evidence that the K27Q/K29Q mutations of Sphk1 could have a protective role in preventing obesity and the related metabolic diseases. Hence, our results contribute to further understanding of the biological functions of Sphk1, which has great pharmaceutical implications.

scholarly journals Role of Sphingosine Kinase/S1P Axis in ECM Remodeling of Cardiac Cells Elicited by Relaxin

2015 ◽  
Vol 29 (1) ◽  
pp. 53-67 ◽  
Author(s):  
Alessia Frati ◽  
Barbara Ricci ◽  
Federica Pierucci ◽  
Silvia Nistri ◽  
Daniele Bani ◽  
...  
Keyword(s):  
Primary Cultures ◽  
Sphingosine Kinase ◽  
Peptide Hormone ◽  
Tissue Growth ◽  
Cardiac Cells ◽  
Sphingolipid Metabolism ◽  
Cardiac Muscle Cells ◽  
Ecm Remodeling ◽  
Cell Proliferation And Differentiation ◽  
Sphingosine 1 Phosphate

Abstract The initiation and progression of heart failure is linked to adverse cardiac remodeling of the extracellular matrix (ECM) during disease mainly through the deregulation of myocardial metalloproteinases (MMPs). Relaxin (RLX), a peptide hormone acting as a physiological cardiac effector, is a key regulator of ECM remodeling in reproductive and nonreproductive tissues. Studying primary cultures of mouse cardiac muscle cells and rat H9c2 cardiomyoblasts, we have obtained evidence for a new signaling pathway activated by RLX to induce ECM remodeling that involves the bioactive sphingolipids sphingosine-1-phosphate (S1P) and ceramide. In both cell populations, recombinant human RLX increased sphingosine kinase activity and S1P formation, whereas sphingomyelin and ceramide content were decreased in [3H]serine-labeled cells. According to the literature, RLX promoted MMP-2 and MMP-9 expression/release. Pharmacological inhibition of sphingolipid metabolism and silencing of sphingosine kinase 1, the enzyme responsible for S1P formation, were able to prevent MMP expression/release elicited by the hormone and induce the expression of tissue inhibitor of MMPs. In addition, we found that sphingolipid signaling is required for the regulation of connective tissue growth factor, a member of the CCN 1–3 family of genes that are involved in cell proliferation and differentiation. Finally, the induction of cardiomyoblast maturation induced by RLX was also found to be counteracted by inhibition of S1P formation. In conclusion, these findings provide a novel mechanism by which RLX acts on cardiac ECM remodeling and cardiac cell differentiation and offer interesting therapeutic options to prevent heart fibrosis and to favor myocardial regeneration.

scholarly journals SphK1 and SphK2, Sphingosine Kinase Isoenzymes with Opposing Functions in Sphingolipid Metabolism

2005 ◽  
Vol 280 (44) ◽  
pp. 37118-37129 ◽  
Author(s):  
Michael Maceyka ◽  
Heidi Sankala ◽  
Nitai C. Hait ◽  
Hervé Le Stunff ◽  
Hong Liu ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Sphingolipid Metabolism

scholarly journals Intracellular Role for Sphingosine Kinase 1 in Intestinal Adenoma Cell Proliferation

2006 ◽  
Vol 26 (19) ◽  
pp. 7211-7223 ◽  
Author(s):  
Masataka Kohno ◽  
Michiko Momoi ◽  
Myat Lin Oo ◽  
Ji-Hye Paik ◽  
Yong-Moon Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Epithelial Cell ◽  
Tumor Cell ◽  
Sphingosine Kinase ◽  
Sphingolipid Metabolism ◽  
Intestinal Tumor ◽  
Epithelial Cell Proliferation ◽  
Tumor Cell Proliferation ◽  
Adenoma Cell

ABSTRACT Sphingosine kinase (Sphk) enzymes are important in intracellular sphingolipid metabolism as well as in the biosynthesis of sphingosine 1-phosphate (S1P), an extracellular lipid mediator. Here, we show that Sphk1 is expressed and is required for small intestinal tumor cell proliferation in Apc Min/+ mice. Adenoma size but not incidence was dramatically reduced in Apc Min/+ Sphk −/ − mice. Concomitantly, epithelial cell proliferation in the polyps was significantly attenuated, suggesting that Sphk1 regulates adenoma progression. Although the S1P receptors (S1P1R, S1P2R, and S1P3R) are expressed, polyp incidence or size was unaltered in Apc Min/+ S1p2r −/ −, Apc Min/+ S1p3r −/ −, and Apc Min/+ S1p1r +/ − bigenic mice. These data suggest that extracellular S1P signaling via its receptors is not involved in adenoma cell proliferation. Interestingly, tissue sphingosine content was elevated in the adenomas of Apc Min/ + Sphk1 −/ − mice, whereas S1P levels were not significantly altered. Concomitantly, epithelial cell proliferation and the expression of the G1/S cell cycle regulator CDK4 and c-myc were diminished in the polyps of Apc Min/ + Sphk1 −/ − mice. In rat intestinal epithelial (RIE) cells in vitro, Sphk1 overexpression enhanced cell cycle traverse at the G1/S boundary. In addition, RIE cells treated with sphingosine but not C6-ceramide exhibited reduced cell proliferation, reduced retinoblastoma protein phosphorylation, and cyclin-dependent kinase 4 (Cdk4) expression. Our findings suggest that Sphk1 plays a critical role in intestinal tumor cell proliferation and that inhibitors of Sphk1 may be useful in the control of intestinal cancer.

scholarly journals Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1030 ◽  
Author(s):  
Michael S. Lee ◽  
Wenji Sun ◽  
Tonya J. Webb
Keyword(s):  
Mantle Cell Lymphoma ◽  
Natural Killer ◽  
Cell Lymphoma ◽  
Sphingosine Kinase ◽  
Nkt Cells ◽  
Sphingolipid Metabolism ◽  
Immune Recognition ◽  
Nkt Cell ◽  
Mantle Cell ◽  
Natural Killer T

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma. Despite being responsive to combination chemotherapy, median survival remains around 5 years due to high rates of relapse. Sphingolipid metabolism regulates MCL survival and proliferation and we found that sphingosine-1-phosphate (S1P) is upregulated in MCL cells. Therapeutic targeting of the S1P1 receptor or knockdown of sphingosine kinase 1 (SK1), the enzyme responsible for generating S1P, in human MCL cells results in a significant increase in Natural Killer T (NKT) cell activation. NKT cells recognize glycolipid antigens presented on CD1d and can reduce MCL tumor burden in vivo. Lipidomic studies identified cardiolipin, which has been reported to bind to CD1d molecules, as being upregulated in SK1 knockdown cells. We found that the pretreatment of antigen presenting cells with cardiolipin leads to increased cytokine production by NKT cell hybridomas. Furthermore, the ability of cardiolipin to activate NKT cells was dependent on the structure of its acyl chains. Collectively, these studies delineate novel pathways important for immune recognition of malignant cells and could lead to the development of new treatments for lymphoma.

scholarly journals Antiestrogenic Effects of the Novel Sphingosine Kinase-2 Inhibitor ABC294640

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5124-5135 ◽  
Author(s):  
James W. Antoon ◽  
Martin D. White ◽  
William D. Meacham ◽  
Evelyn M. Slaughter ◽  
Shannon E. Muir ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Sphingosine Kinase ◽  
Hek293 Cells ◽  
Sphingolipid Metabolism ◽  
Cancer Drug ◽  
The Novel ◽  
Er Positive ◽  
Cancer Tumor ◽  
Positive Breast Cancer

Alterations in sphingolipid metabolism have been shown to contribute to the development of endocrine resistance and breast cancer tumor survival. Sphingosine kinase (SK), in particular, is overexpressed in breast cancer and is a promising target for breast cancer drug development. In this study, we used the novel SK inhibitor ABC294640 as a tool to explore the relationship between SK and estrogen (E2) receptor (ER) signaling in breast cancer cells. Treatment with ABC294640 decreased E2-stimulated ERE-luciferase activity in both MCF-7 and ER-transfected HEK293 cells. Furthermore, the inhibitor reduced E2-mediated transcription of the ER-regulated genes progesterone receptor and SDF-1. Competitive receptor-binding assays revealed that ABC294640 binds in the antagonist ligand-binding domain of the ER, acting as a partial antagonist similar to tamoxifen. Finally, treatment with ABC294640 inhibited ER-positive breast cancer tumor formation in vivo. After 15 d of treatment with ABC294640, tumor volume was reduced by 68.4% (P < 0.05; n = 5) compared with control tumors, with no marked weight loss or illness. Taken together, these results provide strong evidence that this novel SK inhibitor, which had not previously been known to interact with E2 signaling pathways, has therapeutic potential in treating ER-positive breast cancer via inhibition of both SK and ER signaling.

DDRE-19. SPHINGOSINE KINASE 1 AS A THERAPEUTIC TARGET FOR IDH1-R132H mut GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi78-vi78
Author(s):  
Tyrone Dowdy ◽  
Tomohiro Yamasaki ◽  
Lumin Zhang ◽  
Orieta Celiku ◽  
Adrian Lita ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Sphingosine Kinase ◽  
Vital Role ◽  
The Cancer Genome Atlas ◽  
Sphingolipid Metabolism ◽  
Sphingosine Kinase 1 ◽  
Western Blots ◽  
Idh1 R132h ◽  
The Impact

Abstract BACKGROUND Our study aimed to identify vulnerabilities within sphingolipid metabolism with potential to translate to therapeutics. While the vital role of sphingolipids in maintaining rheostat balance and as secondary messengers for signaling pathways (involving proliferation, invasion, migration, and angiogenesis) has been well-documented, their role has not been widely investigated in gliomas. Therefore, metabolic analysis of sphingolipid pathway for IDH1-R132H (IDH1 mut ) glioma cell lines was conducted in order to elucidate susceptible targets. METHODS Global sphingolipid quantification utilized high-throughput LCMS analysis. Pathway protein expression was measured via Western blots in vitro and derived from patients using The Cancer Genome Atlas analysis. RESULTS We probed the impact of decreasing D-2HG on the sphingolipid metabolism after treating a panel of IDH1 mut glioma cells with IDH1-R132H mut inhibitor, AGI5198. This revealed significant downregulation of N,N-dimethylsphingosine (NDMS), C17-sphingosine, and C18-sphinganine. Coincidentally, sphingosine-1-phosphate (S1P) was significantly upregulated in these gliomas. We conducted rational drug screen which revealed that inhibition of SPHK1 with N,N-dimethylsphingosine in combination with C17-sphingosine triggered biostatic dose-response across IDH1 mut gliomas and low impact on IDH WT glioblastoma (GBM) cells. Western analysis revealed that the IDH1 mut gliomas and IDH WT GBM expressed sphingosine kinase-1 (SPHK1). Data also unveiled a discovery that SPHK2 was highly expressed in the GBM cells while remarkably absent in the glioma cells. CONCLUSION Herein, we provide evidence that certain IDH1 mut gliomas present epigenetic silencing of SPHK2 which creates dependency on SPHK1 for S1P; thus, increasing sensitivity to targeting sphingolipid metabolism, and creating susceptibility to proliferation arrest and subsequent cellular death. S1P production has been reported to be elevated particularly for malignant glioblastomas in prior studies; whereas our research revealed that it is relatively low in IDH mut by comparison with IDH WT tumor cells. These findings suggest targeting the sphingolipid metabolism may present a promising strategy to improve survival for patients diagnosed with IDH1 mut gliomas.

Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer

2007 ◽  
Vol 112 (1) ◽  
pp. 41-52 ◽  
Author(s):  
Eugen Ruckhäberle ◽  
Achim Rody ◽  
Knut Engels ◽  
Regine Gaetje ◽  
Gunter von Minckwitz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Microarray Analysis ◽  
Prognostic Significance ◽  
Sphingosine Kinase ◽  
Sphingolipid Metabolism ◽  
Sphingosine Kinase 1

Ceramide and sphingosine-1 phosphate in COPD lungs

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-215892
Author(s):  
Evgeny V Berdyshev ◽  
Karina A Serban ◽  
Kelly S Schweitzer ◽  
Irina A Bronova ◽  
Andrew Mikosz ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Important Determinant ◽  
Inverse Correlation ◽  
Sphingosine Kinase ◽  
Mass Spectrometric ◽  
Sphingolipid Metabolism ◽  
Chronic Obstructive ◽  
Sphingosine Kinase 1 ◽  
Obstructive Pulmonary Disease ◽  
Sphingosine 1 Phosphate

Studies of chronic obstructive pulmonary disease (COPD) using animal models and patient plasma indicate dysregulation of sphingolipid metabolism, but data in COPD lungs are sparse. Mass spectrometric and immunostaining measurements of lungs from 69 COPD, 16 smokers without COPD and 13 subjects with interstitial lung disease identified decoupling of lung ceramide and sphingosine-1 phosphate (S1P) levels and decreased sphingosine kinase-1 (SphK1) activity in COPD. The correlation of ceramide abundance in distal COPD lungs with apoptosis and the inverse correlation between SphK1 activity and presence of emphysema suggest that disruption of ceramide-to-S1P metabolism is an important determinant of emphysema phenotype in COPD.

scholarly journals Identification of circulating sphingosine kinase-related metabolites for prediction of type 2 diabetes

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qi Chen ◽  
Wei Wang ◽  
Ming-Feng Xia ◽  
You-li Lu ◽  
Hua Bian ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Prospective Cohort ◽  
Sphingosine Kinase ◽  
Sphingolipid Metabolism ◽  
Control Group ◽  
Increased Risk ◽  
Sphingosine 1 Phosphate ◽  
Clinical Indices

Abstract Background Sphingosine Kinase (SphK) that catalyzes sphingosine (Sph) to sphingosine 1-phosphate (S1P), plays a key role in both sphingolipid metabolism and cellular signaling. While SphK has been implicated in type 2 diabetes mellitus (T2DM), it is unexplored in humans. Herein, we investigated whether circulating SphK-related metabolites are associated with T2DM incidence in an established prospective cohort. Methods Levels of SphK-related sphingolipid metabolites, including Sph, S1P, dihydrosphingosine (dhSph) and dihydro-S1P (dhS1P) in serum were measured by targeted-lipidomic analyses. By accessing to an established prospective cohort that involves a total of 2486 non-diabetic adults at baseline, 100 subjects who developed T2DM after a mean follow-up of 4.2-years, along with 100 control subjects matched strictly with age, sex, BMI and fasting glucose, were randomly enrolled for the present study. Results Comparison with the control group, medians of serum dhS1P and dhS1P/dhSph ratio at baseline were elevated significantly prior to the onset of T2DM. Each SD increment of dhS1P and dhS1P/dhSph ratio was associated with 53.5% and 54.1% increased risk of incident diabetes, respectively. The predictive effect of circulating dhS1P and dhS1P/dhSph ratio on T2DM incidence was independent of conventional risk factors in multivariate regression models. Furthermore, combination of serum dhS1P and dhS1P/dhSph ratio with conventional clinical indices significantly improved the accuracy of T2DM prediction (AUROC, 0.726), especially for normoglycemic subjects (AUROC, 0.859). Conclusion Circulating levels of dhS1P and dhS1P/dhSph ratio are strongly associated with increased risk of T2DM, and could serve as a useful biomarker for prediction of incident T2DM in normoglycemic populations.

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