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1
Venkataraman, Krishnan, Shobha Thangada, Jason Michaud, Myat Lin Oo, Youxi Ai, Yong-Moon Lee, Mingtao Wu, et al. "Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient." Biochemical Journal 397, no. 3 (July 13, 2006): 461–71. http://dx.doi.org/10.1042/bj20060251.
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Sphingosine 1-phosphate (S1P), produced by Sphks (sphingosine kinases), is a multifunctional lipid mediator that regulates immune cell trafficking and vascular development. Mammals maintain a large concentration gradient of S1P between vascular and extravascular compartments. Mechanisms by which S1P is released from cells and concentrated in the plasma are poorly understood. We recently demonstrated [Ancellin, Colmont, Su, Li, Mittereder, Chae, Stefansson, Liau and Hla (2002) J. Biol. Chem. 277, 6667–6675] that Sphk1 activity is constitutively secreted by vascular endothelial cells. In the present study, we show that among the five Sphk isoforms expressed in endothelial cells, the Sphk-1a isoform is selectively secreted in HEK-293 cells (human embryonic kidney cells) and human umbilical-vein endothelial cells. In sharp contrast, Sphk2 is not secreted. The exported Sphk-1a isoform is enzymatically active and produced sufficient S1P to induce S1P receptor internalization. Wild-type mouse plasma contains significant Sphk activity (179 pmol·min−1·g−1). In contrast, Sphk1−/− mouse plasma has undetectable Sphk activity and approx. 65% reduction in S1P levels. Moreover, human plasma contains enzymatically active Sphk1 (46 pmol·min−1·g−1). These results suggest that export of Sphk-1a occurs under physiological conditions and may contribute to the establishment of the vascular S1P gradient.
2
Wadgaonkar, Raj, Vipul Patel, Natalia Grinkina, Carol Romano, Jing Liu, Yutong Zhao, Saad Sammani, Joe G. N. Garcia, and Viswanathan Natarajan. "Differential regulation of sphingosine kinases 1 and 2 in lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 296, no. 4 (April 2009): L603—L613. http://dx.doi.org/10.1152/ajplung.90357.2008.
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Two mammalian sphingosine kinase (SphK) isoforms, SphK1 and SphK2, possess identical kinase domains but have distinct kinetic properties and subcellular localizations, suggesting each has one or more specific roles in sphingosine-1-phosphate (S1P) generation. Although both kinases use sphingosine as a substrate to generate S1P, the mechanisms controlling SphK activation and subsequent S1P generation during lung injury are not fully understood. In this study, we established a murine lung injury model to investigate LPS-induced lung injury in SphK1 knockout (SphK1−/−) and wild-type (WT) mice. We found that SphK1−/− mice were much more susceptible to LPS-induced lung injury compared with their WT counterparts, quantified by multiple parameters including cytokine induction. Intriguingly, overexpression of WT SphK1 delivered by adenoviral vector to the lungs protected SphK1−/− mice from lung injury and attenuated the severity of the response to LPS. However, adenoviral overexpression of a SphK1 kinase-dead mutant (SphKKD) in SphK1−/− mouse lungs further exacerbated the response to LPS as well as the extent of lung injury. WT SphK2 adenoviral overexpression also failed to provide protection and, in fact, augmented the degree of LPS-induced lung injury. This suggested that, in vascular injury, S1P generated by SphK2 activation plays a distinctly separate role compared with SphK1-dependent S1P generation and survival signaling. Microarray and real-time RT-PCR analysis of SphK1 and SphK2 expression levels during lung injury revealed that, in WT mice, LPS treatment caused significantly enhanced SphK1 expression (∼5×) levels within 6 h, which declined back to baseline levels by 24 h posttreatment. In contrast, expression of SphK2 was gradually induced following LPS treatment and was elevated within 24 h. Collectively, our results for the first time demonstrate distinct functional roles of the two SphK isoforms in the regulation of LPS-induced lung injury.
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Serrano-Sanchez, Martin, Zahra Tanfin, and Denis Leiber. "Signaling Pathways Involved in Sphingosine Kinase Activation and Sphingosine-1-Phosphate Release in Rat Myometrium in Late Pregnancy: Role in the Induction of Cyclooxygenase 2." Endocrinology 149, no. 9 (May 29, 2008): 4669–79. http://dx.doi.org/10.1210/en.2008-1756.
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We investigated the regulation of the sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) axis and its role during pregnancy in the rat myometrium. SphK1 and SphK2 were coexpressed in myometrium during gestation. The levels and activity of SphK1/2 were modest at midgestation (d 12), increased at d 19 and progressively declined to low at postpartum. Similar patterns were observed for the phosphorylation of ERK and protein kinase C (PKC). Inhibition of PKC and ERK reduced SphK1/2 activity. In late pregnancy, levels of cyclooxygenase 2 (COX2) increased in parallel to SphK levels. Using a pharmacological approach, we demonstrated that in primary cultures of myometrial cells from d-19 pregnant rats, induction of COX2 was mediated by 4β-phorbol 12,13-dibutyrate and IL-1β through sequential activation of PKC, ERK1/2, and SphK1. S1P produced by SphK1 was released in the medium. Addition of S1P, IL-1β or 4β-phorbol 12,13-dibutyrate enhanced COX2 levels via Gi protein. Interestingly, S1P was also released by myometrial tissues at late gestation. This event was dependent on PKC/ERK/SphK1. By contrast, in d-12 myometrial tissues, the release of S1P was markedly reduced in association with low levels of SphK1 and COX2. However, prolonged incubation of myometrium from midgestation led to the induction of COX2. This effect was blocked by SphK inhibitors, providing evidence of the close relationship between SphK activity and COX2 induction in rat myometrium. Overall, our findings provided insight into the physiological relevance of the SphK activation and S1P release in uterine smooth muscle during gestation.
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MEACCI, Elisabetta, Francesca CENCETTI, Chiara DONATI, Francesca NUTI, Laura BECCIOLINI, and Paola BRUNI. "Sphingosine kinase activity is required for sphingosine-mediated phospholipase D activation in C2C12 myoblasts." Biochemical Journal 381, no. 3 (July 27, 2004): 655–63. http://dx.doi.org/10.1042/bj20031636.
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Sphingosine (Sph) has been implicated as a modulator of membrane signal transduction systems and as a regulatory element of cardiac and skeletal muscle physiology, but little information is presently available on its precise mechanism of action. Recent studies have shown that sphingosine 1-phosphate (S1P), generated by the action of sphingosine kinase (SphK) on Sph, also possesses biological activity, acting as an intracellular messenger, as well as an extracellular ligand for specific membrane receptors. At present, however, it is not clear whether the biological effects elicited by Sph are attributable to its conversion into S1P. In the present study, we show that Sph significantly stimulated phospholipase D (PLD) activity in mouse C2C12 myoblasts via a previously unrecognized mechanism that requires the conversion of Sph into S1P and its subsequent action as extracellular ligand. Indeed, Sph-induced activation of PLD was inhibited by N,N-dimethyl-D-erythro-sphingosine (DMS), at concentrations capable of specifically inhibiting SphK. Moreover, the crucial role of SphK-derived S1P in the activation of PLD by Sph was confirmed by the observed potentiated effect of Sph in myoblasts where SphK1 was overexpressed, and the attenuated response in cells transfected with the dominant negative form of SphK1. Notably, the measurement of S1P formation in vivo by employing labelled ATP revealed that cell-associated SphK activity in the extracellular compartment largely contributed to the transformation of Sph into S1P, with the amount of SphK released into the medium being negligible. It will be important to establish whether the mechanism of action identified in the present study is implicated in the multiple biological effects elicited by Sph in muscle cells.
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AGEITOS, ARACELI TOBIO, GEETHANI BANDARA, ROSA MUNOZ-CANO, YUZHI YIN, AVANTI DESAI, DEAN METCALFE, and ANA OLIVERA. "Sphingosine Kinase Inhibitors Effectively Inhibit Growth of Mast Cells with D816V-KIT Mutations." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 145.13. http://dx.doi.org/10.4049/jimmunol.198.supp.145.13.
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Abstract Sphingosine-1-phosphate (S1P) is a lipid mediator that promotes cell proliferation and prevents apoptosis in a variety of cells and its increased synthesis by Sphingosine Kinase (SphK) has been associated with oncogenesis and cancer prognosis. Mastocytosis is a disorder characterized by excessive mast cell (MC) proliferation and accumulation in tissues. Treatment therapies for aggressive mastocytosis have to date been partially effective, and thus the search of new pharmacological targets is warranted. We thus investigated the involvement of SphK isoforms (SphK1 and SphK2) and generation of S1P in the regulation of abnormal MC growth. The specific SphK1 and SphK2 inhibitors, SKI-178 and ABC294640, respectively, were used in this study. The effect of SphK1 and SphK2 inhibition on human (LAD2, HMC1.1 and HMC1.2) and murine (P815) neoplastic MC proliferation and survival was evaluated. SphK2 inhibition retarded entry into the cell cycle in all MC lines with no significant effect on cell survival. However, SphK1 inhibition led to cell cycle arrest in G2/M and apoptosis predominantly in MCs carrying D816V-KIT mutation. The effect of SKI-178 was associated with an alteration in the damage response cascade. This included activation of checkpoint kinase 2 (chk2) combined with a depletion of chk1, leading respectively to p53- and caspase2-induced apoptosis and cell cycle arrest mediated by cdc25c depletion. Both SphK inhibitors reduced MC accumulation in an in vivo mouse model of aggressive mastocytosis and the number of cultured bone marrow MCs and MC progenitors from a patient with systemic mastocytosis. These results support further consideration for SphK inhibitors as a cytoreductive strategy in proliferative MC disorders.
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Magli, Elisa, Angela Corvino, Ferdinando Fiorino, Francesco Frecentese, Elisa Perissutti, Irene Saccone, Vincenzo Santagada, Giuseppe Caliendo, and Beatrice Severino. "Design of Sphingosine Kinases Inhibitors: Challenges and Recent Developments." Current Pharmaceutical Design 25, no. 9 (July 9, 2019): 956–68. http://dx.doi.org/10.2174/1381612825666190404115424.
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Background:Sphingosine kinases (SphKs) catalyze the phosphorylation of sphingosine to form the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). S1P is an important lipid mediator with a wide range of biological functions; it is also involved in a variety of diseases such as inflammatory diseases, Alzheimer’s disease and cancer.Methods:This review reports the recent advancement in the research of SphKs inhibitors. Our purpose is also to provide a complete overview useful for underlining the features needed to select a specific pharmacological profile.Discussion:Two distinct mammalian SphK isoforms have been identified, SphK1 and SphK2. These isoforms are encoded by different genes and exhibit distinct subcellular localizations, biochemical properties and functions. SphK1 and SphK2 inhibition can be useful in different pathological conditions.Conclusion:SphK1 and SphK2 have many common features but different and even opposite biological functions. For this reason, several research groups are interested in understanding the therapeutic usefulness of a selective or non-selective inhibitor of SphKs. Moreover, a compensatory mechanism for the two isoforms has been demonstrated, thus leading to the development of dual inhibitors.
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Lynch, Kevin R. "Building a better sphingosine kinase-1 inhibitor." Biochemical Journal 444, no. 1 (April 26, 2012): e1-e2. http://dx.doi.org/10.1042/bj20120567.
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Sphingosine 1-phosphate (S1P) is currently one of the most intensely studied lipid mediators. Interest in S1P has been propelled by the development of fingolimod, an S1P receptor agonist prodrug, which revealed both a theretofore unsuspected role of S1P in lymphocyte trafficking and that such modulation of the immune system achieves therapeutic benefit in multiple sclerosis patients. S1P is synthesized from sphingosine by two SphKs (sphingosine kinases) (SphK1 and SphK2). Manipulation of SphK levels using molecular biology and mouse genetic tools has implicated these enzymes, particularly SphK1, in a variety of pathological processes such as fibrosis, inflammation and cancer progression. The results of such studies have spurred interest in SphK1 as a drug target. In this issue of the Biochemical Journal, Schnute et al. describe a small molecule inhibitor of SphK1 that is both potent and selective. Such chemical tools are essential to learn whether targeting S1P signalling at the level of synthesis is a viable therapeutic strategy.
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Kharel, Yugesh, Mithun Raje, Ming Gao, Amanda M. Gellett, Jose L. Tomsig, Kevin R. Lynch, and Webster L. Santos. "Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate." Biochemical Journal 447, no. 1 (September 12, 2012): 149–57. http://dx.doi.org/10.1042/bj20120609.
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S1P (sphingosine 1-phosphate) is a pleiotropic lipid mediator involved in numerous cellular and physiological functions. Of note among these are cell survival and migration, as well as lymphocyte trafficking. S1P, which exerts its effects via five GPCRs (G-protein-coupled receptors) (S1P1–S1P5), is formed by the action of two SphKs (sphingosine kinases). Although SphK1 is the more intensively studied isotype, SphK2 is unique in it nuclear localization and has been reported to oppose some of the actions ascribed to SphK1. Although several scaffolds of SphK1 inhibitors have been described, there is a scarcity of selective SphK2 inhibitors that are necessary to evaluate the downstream effects of inhibition of this isotype. In the present paper we report a cationic amphiphilic small molecule that is a selective SphK2 inhibitor. In the course of characterizing this compound in wild-type and SphK-null mice, we discovered that administration of the inhibitor to wild-type mice resulted in a rapid increase in blood S1P, which is in contrast with our SphK1 inhibitor that drives circulating S1P levels down. Using a cohort of F2 hybrid mice, we confirmed, compared with wild-type mice, that circulating S1P levels were higher in SphK2-null mice and lower in SphK1-null mice. Thus both SphK1 and SphK2 inhibitors recapitulate the blood S1P levels observed in the corresponding null mice. Moreover, circulating S1P levels mirror SphK2 inhibitor levels, providing a convenient biomarker of target engagement.
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Vessey, Donald A., Luyi Li, Zhu-Qiu Jin, Michael Kelley, Norman Honbo, Jianqing Zhang, and Joel S. Karliner. "A Sphingosine Kinase Form 2 Knockout Sensitizes Mouse Myocardium to Ischemia/Reoxygenation Injury and Diminishes Responsiveness to Ischemic Preconditioning." Oxidative Medicine and Cellular Longevity 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/961059.
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Sphingosine kinase (SphK) exhibits two isoforms, SphK1 and SphK2. Both forms catalyze the synthesis of sphingosine 1-phosphate (S1P), a sphingolipid involved in ischemic preconditioning (IPC). Since the ratio of SphK1 : SphK2 changes dramatically with aging, it is important to assess the role of SphK2 in IR injury and IPC. Langendorff mouse hearts were subjected to IR (30 min equilibration, 50 min global ischemia, and 40 min reperfusion). IPC consisted of 2 min of ischemia and 2 min of reperfusion for two cycles. At baseline, there were no differences in left ventricular developed pressure (LVDP), ± dP/dtmax, and heart rate between SphK2 null (KO) and wild-type (WT) hearts. In KO hearts, SphK2 activity was undetectable, and SphK1 activity was unchanged compared to WT. Total SphK activity was reduced by 53%. SphK2 KO hearts subjected to IR exhibited significantly more cardiac damage (% infarct size) compared with WT (% infarct size); postischemic recovery of LVDP was lower in KO hearts. IPC exerted cardioprotection in WT hearts. The protective effect of IPC against IR was diminished in KO hearts which had much higher infarction sizes (%) compared to the IPC/IR group in control hearts (%). Western analysis revealed that KO hearts had substantial levels of phosphorylated p38 which could predispose the heart to IR injury. Thus, deletion of the SphK2 gene sensitizes the myocardium to IR injury and diminishes the protective effect of IPC.
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Jo, Hyein, Kyeonghee Shim, and Dooil Jeoung. "The Crosstalk between FcεRI and Sphingosine Signaling in Allergic Inflammation." International Journal of Molecular Sciences 23, no. 22 (November 11, 2022): 13892. http://dx.doi.org/10.3390/ijms232213892.
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Sphingolipid molecules have recently attracted attention as signaling molecules in allergic inflammation diseases. Sphingosine-1-phosphate (S1P) is synthesized by two isoforms of sphingosine kinases (SPHK 1 and SPHK2) and is known to be involved in various cellular processes. S1P levels reportedly increase in allergic inflammatory diseases, such as asthma and anaphylaxis. FcεRI signaling is necessary for allergic inflammation as it can activate the SPHKs and increase the S1P level; once S1P is secreted, it can bind to the S1P receptors (S1PRs). The role of S1P signaling in various allergic diseases is discussed. Increased levels of S1P are positively associated with asthma and anaphylaxis. S1P can either induce or suppress allergic skin diseases in a context-dependent manner. The crosstalk between FcεRI and S1P/SPHK/S1PRs is discussed. The roles of the microRNAs that regulate the expression of the components of S1P signaling in allergic inflammatory diseases are also discussed. Various reports suggest the role of S1P in FcεRI-mediated mast cell (MC) activation. Thus, S1P/SPHK/S1PRs signaling can be the target for developing anti-allergy drugs.
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Leiber, Denis, Yoshiko Banno, and Zahra Tanfin. "Exogenous sphingosine 1-phosphate and sphingosine kinase activated by endothelin-1 induced myometrial contraction through differential mechanisms." American Journal of Physiology-Cell Physiology 292, no. 1 (January 2007): C240—C250. http://dx.doi.org/10.1152/ajpcell.00023.2006.
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Sphingosine 1-phosphate (S1P), a bioactive sphingolipid involved in diverse biological processes, is generated by sphingosine kinase (SphK) and acts via intracellular and/or extracellular mechanisms. We used biochemical, pharmacological, and physiological approaches to investigate in rat myometrium the contractile effect of exogenous S1P and the possible contribution of SphK in endothelin-1 (ET-1)-mediated contraction. S1P stimulated uterine contractility (EC50 = 1 μM and maximal response = 5 μM) by a pertussis toxin-insensitive and a phospholipse C (PLC)-independent pathway. Phosphorylated FTY720, which interacts with all S1P receptors, except S1P2 receptors, failed to mimic S1P contractile response, indicating that the effects of S1P involved S1P2 receptors that are expressed in myometrium. Contraction mediated by S1P and ET-1 required extracellular calcium and Rho kinase activation. Inhibition of SphK reduced ET-1-mediated contraction. ET-1, via ETA receptors coupled to pertussis toxin-insensitive G proteins, stimulated SphK1 activity and induced its translocation to the membranes. Myometrial contraction triggered by ET-1 is consecutive to the sequential activation of PLC, protein kinase C, SphK1 and Rho kinase. Prolonged exposure of the myometrium to S1P downregulated S1P2 receptors and abolished the contraction induced by exogenous S1P. However, in these conditions, the tension triggered by ET-1 was not reduced, indicating that SphK activated by ET-1 contributed to its contractile effect via a S1P2 receptor-independent process. Our findings demonstrated that exogenous S1P and SphK activity regulated myometrial contraction and may be of physiological relevance in the regulation of uterine motility during gestation and parturition.
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Pham, Trung H. M., Peter Baluk, Ying Xu, Irina Grigorova, Alex J. Bankovich, Rajita Pappu, Shaun R. Coughlin, Donald M. McDonald, Susan R. Schwab, and Jason G. Cyster. "Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning." Journal of Experimental Medicine 207, no. 1 (December 21, 2009): 17–27. http://dx.doi.org/10.1084/jem.20091619.
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Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P is not defined. We generated mice that expressed Cre from the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and that showed efficient recombination of loxP-flanked genes in lymphatic endothelium. We report that mice with Lyve-1 CRE-mediated ablation of sphingosine kinase (Sphk) 1 and lacking Sphk2 have a loss of S1P in lymph while maintaining normal plasma S1P. In Lyve-1 Cre+ Sphk-deficient mice, lymphocyte egress from LNs and Peyer's patches is blocked. Treatment with pertussis toxin to overcome Gαi-mediated retention signals restores lymphocyte egress. Furthermore, in the absence of lymphatic Sphks, the initial lymphatic vessels in nonlymphoid tissues show an irregular morphology and a less organized vascular endothelial cadherin distribution at cell–cell junctions. Our data provide evidence that lymphatic endothelial cells are an in vivo source of S1P required for lymphocyte egress from LNs and Peyer's patches, and suggest a role for S1P in lymphatic vessel maturation.
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Hafizi, Redona, Faik Imeri, Bisera Stepanovska Tanturovska, Roxana Manaila, Stephanie Schwalm, Sandra Trautmann, Roland H. Wenger, Josef Pfeilschifter, and Andrea Huwiler. "Sphk1 and Sphk2 Differentially Regulate Erythropoietin Synthesis in Mouse Renal Interstitial Fibroblast-like Cells." International Journal of Molecular Sciences 23, no. 11 (May 24, 2022): 5882. http://dx.doi.org/10.3390/ijms23115882.
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Erythropoietin (Epo) is a crucial hormone regulating red blood cell number and consequently the hematocrit. Epo is mainly produced in the kidney by interstitial fibroblast-like cells. Previously, we have shown that in cultures of the immortalized mouse renal fibroblast-like cell line FAIK F3-5, sphingosine 1-phosphate (S1P), by activating S1P1 and S1P3 receptors, can stabilize hypoxia-inducible factor (HIF)-2α and upregulate Epo mRNA and protein synthesis. In this study, we have addressed the role of intracellular iS1P derived from sphingosine kinases (Sphk) 1 and 2 on Epo synthesis in F3-5 cells and in mouse primary cultures of renal fibroblasts. We show that stable knockdown of Sphk2 in F3-5 cells increases HIF-2α protein and Epo mRNA and protein levels, while Sphk1 knockdown leads to a reduction of hypoxia-stimulated HIF-2α and Epo protein. A similar effect was obtained using primary cultures of renal fibroblasts isolated from wildtype mice, Sphk1−/−, or Sphk2−/− mice. Furthermore, selective Sphk2 inhibitors mimicked the effect of genetic Sphk2 depletion and also upregulated HIF-2α and Epo protein levels. The combined blockade of Sphk1 and Sphk2, using Sphk2−/− renal fibroblasts treated with the Sphk1 inhibitor PF543, resulted in reduced HIF-2α and Epo compared to the untreated Sphk2−/− cells. Exogenous sphingosine (Sph) enhanced HIF-2α and Epo, and this was abolished by the combined treatment with the selective S1P1 and S1P3 antagonists NIBR-0213 and TY52156, suggesting that Sph was taken up by cells and converted to iS1P and exported to then act in an autocrine manner through S1P1 and S1P3. The upregulation of HIF-2α and Epo synthesis by Sphk2 knockdown was confirmed in the human hepatoma cell line Hep3B, which is well-established to upregulate Epo production under hypoxia. In summary, these data show that sphingolipids have diverse effects on Epo synthesis. While accumulation of intracellular Sph reduces Epo synthesis, iS1P will be exported to act through S1P1+3 to enhance Epo synthesis. Furthermore, these data suggest that selective inhibition of Sphk2 is an attractive new option to enhance Epo synthesis and thereby to reduce anemia development in chronic kidney disease.
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Nishiuma, Teruaki, Yoshihiro Nishimura, Taro Okada, Emi Kuramoto, Yoshikazu Kotani, Saleem Jahangeer, and Shun-ichi Nakamura. "Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model." American Journal of Physiology-Lung Cellular and Molecular Physiology 294, no. 6 (June 2008): L1085—L1093. http://dx.doi.org/10.1152/ajplung.00445.2007.
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Sphingosine 1-phosphate (S1P) produced by sphingosine kinase (SPHK) is implicated in acute immunoresponses, however, mechanisms of SPHK/S1P signaling in the pathogenesis of bronchial asthma are poorly understood. In this study, we hypothesized that SPHK inhibition could ameliorate lung inflammation in ovalbumin (OVA)-challenged mouse lungs. Six- to eight-week-old C57BL/6J mice were sensitized and exposed to OVA for 3 consecutive days. Twenty-four hours later, mice lungs and bronchoalveolar lavage (BAL) fluid were analyzed. For an inhibitory effect, either of the two different SPHK inhibitors, N, N-dimethylsphingosine (DMS) or SPHK inhibitor [SK-I; 2-( p-hydroxyanilino)-4-( p-chlorophenyl) thiazole], was nebulized for 30 min before OVA inhalation. OVA inhalation caused S1P release into BAL fluid and high expression of SPHK1 around bronchial epithelial walls and inflammatory areas. DMS or SK-I inhalation resulted in a decrease in S1P amounts in BAL fluid to basal levels, accompanied by decreased eosinophil infiltration and peroxidase activity. The extent of inhibition caused by DMS inhalation was higher than that caused by SK-I. Like T helper 2 (Th2) cytokine release, OVA inhalation-induced increase in eotaxin expression was significantly suppressed by DMS pretreatment both at protein level in BAL fluid and at mRNA level in lung homogenates. Moreover, bronchial hyperresponsiveness to inhaled methacholine and goblet cell hyperplasia were improved by SPHK inhibitors. These data suggest that the inhibition of SPHK affected acute eosinophilic inflammation induced in antigen-challenged mouse model and that targeting SPHK may provide a novel therapeutic tool to treat bronchial asthma.
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Matsumoto, Kenji, Yoshiko Banno, Takashi Murate, Yukihiro Akao, and Yoshinori Nozawa. "Localization of Sphingosine Kinase-1 in Mouse Sperm Acrosomes." Journal of Histochemistry & Cytochemistry 53, no. 2 (February 2005): 243–47. http://dx.doi.org/10.1369/jhc.4b6507.2005.
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Sphingosine kinase (SPHK) catalyzes sphingosine phosphorylation to form a bioactive lipid mediator, sphingosine-1-phosphate (S1P). In the current study, we report the presence of SPHK-1 in mouse spermatozoa. SPHK-1 was localized to the acrosomes of spermatozoa, and its expression was proven by RT-PCR and Western blot analysis. SPHK activity of mouse spermatozoa was 18.1 pmol/min/mg protein. Furthermore, we identified the presence of the S1P receptors S1P1, S1P2, S1P3, and S1P5, in mouse spermatozoa by RT-PCR. These results suggest that S1P produced by SPHK-1 would play a role in the acrosomal reaction through S1P receptors.
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Ishay, Yuval, Dvorah Rotnemer-Golinkin, and Yaron Ilan. "The role of the sphingosine axis in immune regulation: A dichotomy in the anti-inflammatory effects between sphingosine kinase 1 and sphingosine kinase 2-dependent pathways." International Journal of Immunopathology and Pharmacology 35 (January 2021): 205873842110532. http://dx.doi.org/10.1177/20587384211053274.
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Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+ T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.
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Qin, Zhiqiang, Lu Dai, Karlie Plaisance-Bonstaff, Can Senkal, Wenxue Wang, Thomas M. Reske, Luis Del Valle, et al. "Targeting Sphingosine Kinase Induces Apoptosis and Regression Of Virus-Associated Lymphoma In Vivo." Blood 122, no. 21 (November 15, 2013): 4414. http://dx.doi.org/10.1182/blood.v122.21.4414.4414.
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Background and Specific Aim Sphingosine kinase (SphK) is overexpressed by a variety of cancers, and its phosphorylation of sphingosine results in accumulation of sphingosine-1-phosphate (S1P) and activation of anti-apoptotic signal transduction. Existing data indicate a role for S1P in viral pathogenesis, but roles for SphK and S1P in virus-associated cancer progression have not been defined. The Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of primary effusion lymphoma (PEL)—a rapidly progressive tumor arising in body cavities which incurs a median survival time of around 6 months with standard therapeutic approaches. ABC294640 is an orally bioavailable small molecule inhibitor of SphK under evaluation in early-phase clinical trials, although no pre-clinical or clinical data are available for this agent for hematologic or virus-associated malignancies. Therefore, we sought to determine whether ABC294640 displays inhibitory effects for HIV/KSHV+ patient-derived PEL cells in vitro and in vivo, as well as potential mechanisms through which SphK regulates KSHV pathogenesis. Methodology Complementary in vitro assays were undertaken using RNAi and ABC294640 for targeting SphK1 and SphK2 in HIV/KSHV+ patient-derived PEL cell lines (uninfected B cell tumor lines were used as controls). qRT-PCR and immunoblots were used to quantify KSHV gene expression and signal transduction, respectively; MTT assays and flow cytometry were used to assess metabolic activity and apoptosis; and mass spectrometry was used to quantify different bioactive sphingolipid intermediates associated with SphK activity. ABC294640 was used in a murine PEL xenograft model to assess the effects of SphK inhibition on KSHV+ lymphoma progression in vivo. Results and Conclusions We find that targeting SphK induces caspase cleavage and apoptosis for KSHV+ patient-derived PEL cells in the presence or absence of co-infection with the Epstein-Barr virus (EBV), whereas uninfected B cell tumor lines are less readily affected. Validating these results, we find that systemic administration of ABC294640 induces tumor regression in the PEL xenograft model. Complimentary ex vivo and in vitro analyses revealed that ABC294640 suppresses constitutive signal transduction associated with proliferation and survival of PEL cells, and increases intracellular accumulation of pro-apoptotic sphingolipid intermediates as well as KSHV lytic genes previously associated with cancer cell death. These results justify additional studies to identify mechanisms for SphK and S1P regulation of virus-associated PEL pathogenesis. Importantly, they also justify evaluation of ABC294640 in clinical trials as a single agent, or in combination with existing approaches, for the treatment of PEL and possibly other malignancies associated with oncogenic viruses. Disclosures: No relevant conflicts of interest to declare.
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Allende, Maria L., Teiji Sasaki, Hiromichi Kawai, Ana Olivera, Yide Mi, Gerhild van Echten-Deckert, Richard Hajdu, et al. "Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720." Journal of Biological Chemistry 279, no. 50 (September 30, 2004): 52487–92. http://dx.doi.org/10.1074/jbc.m406512200.
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Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.
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Techarang, Tachpon, Pitchanee Jariyapong, and Chuchard Punsawad. "Role of sphingosine kinase and sphingosine-1-phosphate receptor in the liver pathology of mice infected with Plasmodium berghei ANKA." PLOS ONE 17, no. 3 (March 25, 2022): e0266055. http://dx.doi.org/10.1371/journal.pone.0266055.
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Decreased serum sphingosine 1-phosphate (S1P) has been reported in severe malaria patients, but the expression of receptors and enzymes associated with S1P has not been investigated in the liver of malaria patients. Therefore, this study aimed to investigate the expression of sphingosine kinase (SphK) and S1P receptors (S1PRs) in the liver of malaria-infected mice. C57BL/6 male mice were divided into a control group (n = 10) and a Plasmodium berghei (PbA)-infected group (n = 10). Mice in the malaria group were intraperitoneally injected with 1×106 P. berghei ANKA-infected red blood cells, whereas control mice were intraperitoneally injected with normal saline. Liver tissues were collected on Day 13 of the experiment to evaluate histopathological changes by hematoxylin and eosin staining and to investigate SphK and S1PR expression by immunohistochemistry and real-time PCR. Histological examination of liver tissues from the PbA-infected group revealed sinusoidal dilatation, hemozoin deposition, portal tract inflammation and apoptotic hepatocytes, which were absent in the control group. Immunohistochemical staining showed significant increases in the expression of SphK1 and SphK2 and significant decreases in the expression of S1PR1, S1PR2, and S1PR3 in the endothelium, hepatocytes, and Kupffer cells in liver tissue from the PbA-infected group compared with the control group. Real-time PCR analysis showed the upregulation of SphK1 and the downregulation of S1PR1, S1PR2, and S1PR3 in the liver in the PbA-infected group compared with the control group. In conclusion, this study demonstrates for the first time that SphK1 mRNA expression is upregulated and that S1PR1, S1PR2, and S1PR3 expression is decreased in the liver tissue of PbA-infected mice. Our findings suggest that the decreased levels of S1PR1, S1PR2, and S1PR3 might play an important role in liver injury during malaria infection.
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FUJITA, Toshitada, Taro OKADA, Shun HAYASHI, Saleem JAHANGEER, Noriko MIWA, and Shun-ichi NAKAMURA. "δ-Catenin/NPRAP (neural plakophilin-related armadillo repeat protein) interacts with and activates sphingosine kinase 1." Biochemical Journal 382, no. 2 (August 24, 2004): 717–23. http://dx.doi.org/10.1042/bj20040141.
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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.
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Terao, Ryo, Megumi Honjo, Takashi Ueta, Hideru Obinata, Takashi Izumi, Makoto Kurano, Yutaka Yatomi, Hideto Koso, Sumiko Watanabe, and Makoto Aihara. "Light Stress-Induced Increase of Sphingosine 1-Phosphate in Photoreceptors and Its Relevance to Retinal Degeneration." International Journal of Molecular Sciences 20, no. 15 (July 26, 2019): 3670. http://dx.doi.org/10.3390/ijms20153670.
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Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammation and angiogenesis. In this study, we investigated the possible involvement of S1P in the pathology of light-induced retinal degeneration in vivo and in vitro. The intracellular S1P and sphingosine kinase (SphK) activity in a photoreceptor cell line (661W cells) was significantly increased by exposure to light. The enhancement of SphK1 expression was dependent on illumination, and all-trans-retinal significantly promoted SphK1 expression. S1P treatment reduced protein kinase B (Akt) phosphorylation and increased the protein expression of cleaved caspase-3, and induced photoreceptor cell apoptosis. In vivo, light exposure enhanced the expression of SphK1 in the outer segments of photoreceptors. Intravitreal injection of a SphK inhibitor significantly suppressed the thinning of the outer nuclear layer and ameliorated the attenuation of the amplitudes of a-waves and b-waves of electroretinograms during light-induced retinal degeneration. These findings imply that light exposure induces the synthesis of S1P in photoreceptors by upregulating SphK1, which is facilitated by all-trans-retinal, causing retinal degeneration. Inhibition of this enhancement may be a therapeutic target of outer retinal degeneration, including age-related macular degeneration.
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Viriyavejakul, Parnpen, and Chuchard Punsawad. "Overexpression of Sphingosine Kinase-1 and Sphingosine-1-Phosphate Receptor-3 in Severe Plasmodium falciparum Malaria with Pulmonary Edema." BioMed Research International 2020 (February 26, 2020): 1–7. http://dx.doi.org/10.1155/2020/3932569.
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Pulmonary edema (PE) is a major cause of pulmonary manifestations of severe Plasmodium falciparum malaria and is usually associated with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The sphingosine kinase-1 (SphK-1)/sphingosine-1-phosphate receptor-3 (S1PR-3) pathway has recently been reported to affect the pathogenesis of lung injury, but the expression of these proteins in the lungs of severe P. falciparum malaria patients has not been investigated. The cellular expression of SphK-1 and S1PR-3 in lung tissues from autopsied patients with P. falciparum malaria was investigated using immunohistochemistry (IHC). Lung tissues from patients who died of severe P. falciparum malaria were classified into two groups based on histopathological findings: those with PE (18 patients) and those without PE (non-PE, 19 patients). Ten samples of normal lung tissues were used as the control group. The protein expression levels of SphK-1 and S1PR-3 were significantly upregulated in endothelial cells (ECs), alveolar epithelial cells, and alveolar macrophages (AMs) in the lungs of severe P. falciparum malaria patients with PE compared to those in the non-PE and control groups (all p<0.001). In addition, the SphK-1 and S1PR-3 expression levels were significantly positively correlated in pulmonary ECs (rs=0.922, p<0.001), alveolar epithelial cells (rs=0.995, p<0.001), and AMs (rs=0.969, p<0.001). In conclusion, both the SphK-1 and S1PR-3 proteins were overexpressed in the lung tissues of severe P. falciparum malaria patients with PE, suggesting that SphK-1 and S1PR-3 mediate the pathogenesis of PE in severe malaria. Targeting the regulation of SphK-1 and/or S1PR-3 may be an approach to treat pulmonary complications in severe P. falciparum patients.
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Kohno, Masataka, Michiko Momoi, Myat Lin Oo, Ji-Hye Paik, Yong-Moon Lee, Krishnan Venkataraman, Youxi Ai, et al. "Intracellular Role for Sphingosine Kinase 1 in Intestinal Adenoma Cell Proliferation." Molecular and Cellular Biology 26, no. 19 (October 1, 2006): 7211–23. http://dx.doi.org/10.1128/mcb.02341-05.
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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.
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Ebenezer, David L., Evgeny V. Berdyshev, Irina A. Bronova, Yuru Liu, Chinnaswamy Tiruppathi, Yulia Komarova, Elizaveta V. Benevolenskaya, et al. "Pseudomonas aeruginosa stimulates nuclear sphingosine-1-phosphate generation and epigenetic regulation of lung inflammatory injury." Thorax 74, no. 6 (February 5, 2019): 579–91. http://dx.doi.org/10.1136/thoraxjnl-2018-212378.
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IntroductionDysregulated sphingolipid metabolism has been implicated in the pathogenesis of various pulmonary disorders. Nuclear sphingosine-1-phosphate (S1P) has been shown to regulate histone acetylation, and therefore could mediate pro-inflammatory genes expression.MethodsProfile of sphingolipid species in bronchoalveolar lavage fluids and lung tissue of mice challenged with Pseudomonas aeruginosa (PA) was investigated. The role of nuclear sphingosine kinase (SPHK)2 and S1P in lung inflammatory injury by PA using genetically engineered mice was determined.ResultsGenetic deletion of Sphk2, but not Sphk1, in mice conferred protection from PA-mediated lung inflammation. PA infection stimulated phosphorylation of SPHK2 and its localisation in epithelial cell nucleus, which was mediated by protein kinase C (PKC) δ. Inhibition of PKC δ or SPHK2 activity reduced PA-mediated acetylation of histone H3 and H4, which was necessary for the secretion of pro-inflammatory cytokines, interleukin-6 and tumour necrosis factor-α. The clinical significance of the findings is supported by enhanced nuclear localisation of p-SPHK2 in the epithelium of lung specimens from patients with cystic fibrosis (CF).ConclusionsOur studies define a critical role for nuclear SPHK2/S1P signalling in epigenetic regulation of bacterial-mediated inflammatory lung injury. Targeting SPHK2 may represent a potential strategy to reduce lung inflammatory pulmonary disorders such as pneumonia and CF.
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Paugh, Steven W., Barbara S. Paugh, Mohamed Rahmani, Dmitri Kapitonov, Jorge A. Almenara, Tomasz Kordula, Sheldon Milstien, et al. "A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia." Blood 112, no. 4 (August 15, 2008): 1382–91. http://dx.doi.org/10.1182/blood-2008-02-138958.
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Abstract The potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P), is produced by 2 sphingosine kinase isoenzymes, SphK1 and SphK2. Expression of SphK1 is up-regulated in cancers, including leukemia, and associated with cancer progression. A screen of sphingosine analogs identified (2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol, designated SK1-I (BML-258), as a potent, water-soluble, isoenzyme-specific inhibitor of SphK1. In contrast to pan-SphK inhibitors, SK1-I did not inhibit SphK2, PKC, or numerous other protein kinases. SK1-I decreased growth and survival of human leukemia U937 and Jurkat cells, and enhanced apoptosis and cleavage of Bcl-2. Lethality of SK1-I was reversed by caspase inhibitors and by expression of Bcl-2. SK1-I not only decreased S1P levels but concomitantly increased levels of its proapoptotic precursor ceramide. Conversely, S1P protected against SK1-I–induced apoptosis. SK1-I also induced multiple perturbations in activation of signaling and survival-related proteins, including diminished phosphorylation of ERK1/2 and Akt. Expression of constitutively active Akt protected against SK1-I–induced apoptosis. Notably, SK1-I potently induced apoptosis in leukemic blasts isolated from patients with acute myelogenous leukemia but was relatively sparing of normal peripheral blood mononuclear leukocytes. Moreover, SK1-I markedly reduced growth of AML xenograft tumors. Our results suggest that specific inhibitors of SphK1 warrant attention as potential additions to the therapeutic armamentarium in leukemia.
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Shamshiddinova, Maftuna, Shokhid Gulyamov, Hee-Jung Kim, Seo-Hyeon Jung, Dong-Jae Baek, and Yong-Moon Lee. "A Dansyl-Modified Sphingosine Kinase Inhibitor DPF-543 Enhanced De Novo Ceramide Generation." International Journal of Molecular Sciences 22, no. 17 (August 25, 2021): 9190. http://dx.doi.org/10.3390/ijms22179190.
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Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P is linked to a pathological outcome with inflammation, cancer metastasis, or angiogenesis, etc. In this regard, SPHK/S1P axis regulation has been a specific issue in the anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhancing serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs, which eventually induced an unusual environment with a high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase), which contributes a partial increase in Cers. Collectively, a dansyl-modified DPF-543 relatively enhanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.
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Dowdy, Tyrone, Lumin Zhang, Orieta Celiku, Sriya Movva, Victor Ruiz-Rodado, Adrian Lita, and Mioara Larion. "DDRE-20. TARGETING SPHINGOLIPID PATHWAY REVEALS VULNERABILITY IN IDH1MUT GLIOMA." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i10. http://dx.doi.org/10.1093/noajnl/vdab024.042.
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Abstract BACKGROUND While central carbon metabolism has been studied extensively in cancer, lipidomic research is sparse. Sphingolipids participate in cellular functions including secondary messengers, lymphocyte trafficking, inflammation, angiogenesis, migration, proliferation, necrosis and apoptosis, thus highlighting the importance of understanding their role to tumor phenotype. Our investigation into metabolic alterations involving sphingolipid pathway in patient-derived IDH1mut glioma cultures aimed to identify points of metabolic vulnerability. METHODS Dysregulation of sphingolipid metabolism was interrogated for brain tumor cultures via LCMS. Expression of enzymes within the pathway was assessed for IDHmut 1/2 and IDHWT glioblastoma patient cohorts via The Cancer Genome Atlas (TCGA) analysis and Western blot for tumor cultures. Biostatic drug response was examined via viability and cytotoxicity assays. RESULTS We probed the effect that decreasing D-2HG levels with IDH1mut inhibitor (AGI5198) treatments had on sphingolipid metabolism in tumor cultures. The probe revealed N,N-dimethylsphingosine (NDMS), and sphingosine were significantly elevated, while sphingosine-1-phosphate (S1P) was downregulated in IDH1mut cultures following treatment. Drug panel screening revealed that SPHK inhibitor (SPHKi), N,N-dimethylsphingosine in combination with sphingosine triggered lethal dose-dependent response in IDH1mut cultures; contrary to IDHWT. Westerns presented differential expression of SPHK1 and SPHK2 in IDHWT glioblastoma cells, while IDHmut exclusively expressed SPHK1. CONCLUSION This novel discovery showed how targeting sphingolipid metabolism in IDH1mut gliomas presents therapeutic implications. Elevated S1P was reported particularly for malignant glioblastomas in prior studies; whereas our research revealed relatively low S1P in the IDHmut compared with IDHWT cultures. In addition to reduced or silenced expression of SPHK2, we postulate that S1P levels in IDHmut gliomas might be closer to a critical threshold allowing treatment with SPHK1i to effectively suspend proliferation and anti-apoptotic defense mechanisms. Our findings revealed that the manipulation of pivotal, endogenous sphingolipids can ultimately trigger apoptosis in IDHmut gliomas. Future studies will probe these targets in preclinical models.
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Sukocheva, Olga A., Lijun Wang, Nathaniel Albanese, Stuart M. Pitson, Mathew A. Vadas, and Pu Xia. "Sphingosine Kinase Transmits Estrogen Signaling in Human Breast Cancer Cells." Molecular Endocrinology 17, no. 10 (October 1, 2003): 2002–12. http://dx.doi.org/10.1210/me.2003-0119.
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Abstract Current understanding of cytoplasmic signaling pathways that mediate estrogen action in human breast cancer is incomplete. Here we report that treatment with 17β-estradiol (E2) activates a novel signaling pathway via activation of sphingosine kinase (SphK) in MCF-7 breast cancer cells. We found that E2 has dual actions to stimulate SphK activity, i.e. a rapid and transient activation mediated by putative membrane G protein-coupled estrogen receptors (ER) and a delayed but prolonged activation relying on the transcriptional activity of ER. The E2-induced SphK activity consequently activates downstream signal cascades including intracellular Ca2+ mobilization and Erk1/2 activation. Enforced expression of human SphK type 1 gene in MCF-7 cells resulted in increases in SphK activity and cell growth. Moreover, the E2-dependent mitogenesis were highly promoted by SphK overexpression as determined by colony growth in soft agar and solid focus formation. In contrast, expression of SphKG82D, a dominant-negative mutant SphK, profoundly inhibited the E2-mediated Ca2+ mobilization, Erk1/2 activity and neoplastic cell growth. Thus, our data suggest that SphK activation is an important cytoplasmic signaling to transduce estrogen-dependent mitogenic and carcinogenic action in human breast cancer cells.
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Schnute, Mark E., Matthew D. McReynolds, Tom Kasten, Matthew Yates, Gina Jerome, John W. Rains, Troii Hall, et al. "Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1." Biochemical Journal 444, no. 1 (April 26, 2012): 79–88. http://dx.doi.org/10.1042/bj20111929.
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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.
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Rigogliuso, Salvatrice, Chiara Donati, Donata Cassarà, Simona Taverna, Monica Salamone, Paola Bruni, and Maria Letizia Vittorelli. "An Active Form of Sphingosine Kinase-1 Is Released in the Extracellular Medium as Component of Membrane Vesicles Shed by Two Human Tumor Cell Lines." Journal of Oncology 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/509329.
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Expression of sphingosine kinase-1 (SphK-1) correlates with a poor survival rate of tumor patients. This effect is probably due to the ability of SphK-1 to be released into the extracellular medium where it catalyzes the biosynthesis of sphingosine-1-phosphate (S1P), a signaling molecule endowed with profound proangiogenic effects. SphK-1 is a leaderless protein which is secreted by an unconventional mechanism. In this paper, we will show that in human hepatocarcinoma Sk-Hep1 cells, extracellular signaling is followed by targeting the enzyme to the cell surface and parallels targeting of FGF-2 to the budding vesicles. We will also show that SphK-1 is present in a catalitycally active form in vesicles shed by SK-Hep1 and human breast carcinoma 8701-BC cells. The enzyme substrate sphingosine is present in shed vesicles where it is produced by neutral ceramidase. Shed vesicles are therefore a site for S1P production in the extracellular medium and conceivably also within host cell following vesicle endocytosis.
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Kim, Sungjin, and Derek Sieburth. "FSHR-1/GPCR Regulates the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans." Genetics 214, no. 2 (December 4, 2019): 409–18. http://dx.doi.org/10.1534/genetics.119.302947.
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The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In Caenorhabditis elegans, the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPRmt. The mechanisms by which mitochondrial stress is sensed by neurons and transmitted to distal tissues are not fully understood. Here, we identify a role for the conserved follicle-stimulating hormone G protein-coupled receptor, FSHR-1, in promoting UPRmt activation. Genetic deficiency of fshr-1 severely attenuates UPRmt activation and organism-wide survival in response to mitochondrial stress. FSHR-1 functions in a common genetic pathway with SPHK-1/sphingosine kinase to promote UPRmt activation, and FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine. Through tissue-specific rescue assays, we show that FSHR-1 functions in neurons to activate the UPRmt, to promote mitochondrial association of SPHK-1 in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that FSHR-1 functions cell nonautonomously in neurons to activate UPRmt upstream of SPHK-1 signaling in the intestine.
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Jolly, Puneet S., Meryem Bektas, Ana Olivera, Claudia Gonzalez-Espinosa, Richard L. Proia, Juan Rivera, Sheldon Milstien, and Sarah Spiegel. "Transactivation of Sphingosine-1–Phosphate Receptors by FcεRI Triggering Is Required for Normal Mast Cell Degranulation and Chemotaxis." Journal of Experimental Medicine 199, no. 7 (April 5, 2004): 959–70. http://dx.doi.org/10.1084/jem.20030680.
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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.
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Gupta, Preeti, Aaliya Taiyab, Afzal Hussain, Mohamed F. Alajmi, Asimul Islam, and Md Imtaiyaz Hassan. "Targeting the Sphingosine Kinase/Sphingosine-1-Phosphate Signaling Axis in Drug Discovery for Cancer Therapy." Cancers 13, no. 8 (April 15, 2021): 1898. http://dx.doi.org/10.3390/cancers13081898.
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Sphingolipid metabolites have emerged as critical players in the regulation of various physiological processes. Ceramide and sphingosine induce cell growth arrest and apoptosis, whereas sphingosine-1-phosphate (S1P) promotes cell proliferation and survival. Here, we present an overview of sphingolipid metabolism and the compartmentalization of various sphingolipid metabolites. In addition, the sphingolipid rheostat, a fine metabolic balance between ceramide and S1P, is discussed. Sphingosine kinase (SphK) catalyzes the synthesis of S1P from sphingosine and modulates several cellular processes and is found to be essentially involved in various pathophysiological conditions. The regulation and biological functions of SphK isoforms are discussed. The functions of S1P, along with its receptors, are further highlighted. The up-regulation of SphK is observed in various cancer types and is also linked to radio- and chemoresistance and poor prognosis in cancer patients. Implications of the SphK/S1P signaling axis in human pathologies and its inhibition are discussed in detail. Overall, this review highlights current findings on the SphK/S1P signaling axis from multiple angles, including their functional role, mechanism of activation, involvement in various human malignancies, and inhibitor molecules that may be used in cancer therapy.
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Giusto, Kiersten, and Charles R. Ashby. "Investigating the Et-1/SphK/S1P Pathway as a Novel Approach for the Prevention of Inflammation-Induced Preterm Birth." Current Pharmaceutical Design 24, no. 9 (May 18, 2018): 983–88. http://dx.doi.org/10.2174/1381612824666180130122739.
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Background: Preterm birth (PTB), defined as birth before 37 completed weeks of gestation, occurs in up to 18 percent of births worldwide and accounts for the majority of perinatal morbidity and mortality. While the single most common cause of PTB has been identified as inflammation, safe and effective pharmacotherapy to prevent PTB has yet to be developed. Methods: Our group has used an in vivo model of inflammation-driven PTB, biochemical methods, pharmacological approaches, a novel endothelin receptor antagonist that we synthesized and RNA knockdown to help establish the role of endothelin-1 (ET-1) in inflammation-associated PTB. Further, we have used our in vivo model to test whether sphingosine kinase, which acts downstream of ET-1, plays a role in PTB. Results: We have shown that levels of endothelin converting enzyme-1 (ECE-1) and ET-1 are increased when PTB is induced in timed pregnant mice with lipopolysaccharide (LPS) and that blocking ET-1 action, pharmacologically or using ECE-1 RNA silencing, rescues LPS-induced mice from PTB. ET-1 activates the sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) pathway. S1P, in turn, is an important signaling molecule in the proinflammatory response. Interestingly, we have shown that SphK inhibition also prevents LPS-induced PTB in timed pregnant mice. Further, we showed that SphK inhibition suppresses the ECE-1/ET-1 axis, implicating positive feedback regulation of the SphK/S1P/ECE-1/ET-1 axis. Conclusion: The ET-1/SphK/SIP pathway is a potential pharmacotherapeutic target for the prevention of PTB.
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Chakraborty, Paramita, Krishnamurthy Thyagarajan, Shilpak Chatterjee, Shanmugam Panneer Selvam, Besim Ogretmen, and Shikhar Mehrotra. "SphK1/S1P Axis Regulate PPARγ Levels to Program Metabolically Fit Anti-Tumor T Cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 179.9. http://dx.doi.org/10.4049/jimmunol.200.supp.179.9.
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Abstract Metabolic competition with highly glycolytic tumor and overcoming tumor-induced suppression are prerequisites for achieving prolonged tumor control by adoptive T cell therapy (ACT). Given the importance of sphingosine-1-phosphate (S1P) signaling that are independent of immune cell trafficking, we evaluated if altering sphingosine kinase (SphK) mediated S1P level have benefits for anti-tumor T cell response. A comparison of melanoma epitope gp100 reactive T cell receptor transgenic pMel vs. pMel-SphK1−/− mice derived splenic T cells showed better control of subcutaneously established murine B16-F10 melanoma, increased infiltration at the tumor site with activated pMel-SphK1−/− T cells. Additionally, pMel-Sphk1−/−T cells also exhibited enhanced recall response tracked in different organs after secondary antigen exposure. Mechanistically, we found that attenuation of SphK1/S1P signaling results in higher Sirt1 (an NAD+ dependent protein deacetylase) activity, lower PPARγ activity and higher retention of FOXO1 in the nucleus. While higher nuclear localization of FOXO1 regulates higher migration of SphK1−/− CD8+ T cells, lower PPARγ activity endows them with increased ability to use their stored lipid content even in starved condition and decreased iTreg generation. Owing to their efficacious utilization of lipid as fuel, Sphk1−/− T cells persist longer in nutrient deprived tumor microenvironment. In reciprocal studies, endogenous production of S1P in Sphk1−/− T cells (transfected with WT Sphk1 vector) enhanced PPARγ expression and thereby reversed their phenotype in terms of iTreg generation and lipid utilization. Overall, these data highlight that strategies targeting SphK/S1P axis improves efficacy of ACT.
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Dai, Lan, Yanfei Qi, Jinbiao Chen, Dominik Kaczorowski, Wen Di, Wei Wang, and Pu Xia. "Sphingosine Kinase (SphK) 1 and SphK2 Play Equivalent Roles in Mediating Insulin's Mitogenic Action." Molecular Endocrinology 28, no. 2 (February 1, 2014): 197–207. http://dx.doi.org/10.1210/me.2013-1237.
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Wang, Liangrong, Feifei Chen, Yafei Pan, Lina Lin, and Xiangqing Xiong. "Effects of FTY720 on Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats." Mediators of Inflammation 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/5301312.
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Background. Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid mediator involved in modulating inflammatory process. We investigated the effects of FTY720, a structural analogue of S1P after phosphorylation, on lung injury induced by hindlimb ischemia reperfusion (IR) in rats. Methods. Fifty Sprague-Dawley rats were divided into groups SM, IR, F3, F5, and F10. Group SM received sham operation, and bilateral hindlimb IR was established in group IR. The rats in groups F3, F5, and F10 were pretreated with 3, 5, and 10 mg/kg/d FTY720 for 7 days before IR. S1P lyase (S1PL), sphingosine kinase (SphK) 1, and SphK2 mRNA expressions, wet/dry weight (W/D), and polymorphonuclear/alveolus (P/A) in lung tissues were detected, and the lung injury score was evaluated. Results. W/D, P/A, and mRNA expressions of S1PL, SphK1, and SphK2 were higher in group IR than in group SM, while these were decreased in both groups F5 and F10 as compared to IR (p<0.05). The lung tissue presented severe lesions in group IR, which were attenuated in groups F5 and F10 with lower lung injury scores than in group IR (p<0.05). Conclusions. FTY720 pretreatment could attenuate lung injury induced by hindlimb IR by modulating S1P metabolism and decreasing pulmonary neutrophil infiltration.
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Okada, Taro, Guo Ding, Hirofumi Sonoda, Taketoshi Kajimoto, Yuki Haga, Ali Khosrowbeygi, Sanyang Gao, Noriko Miwa, Saleem Jahangeer, and Shun-ichi Nakamura. "Involvement of N-terminal-extended Form of Sphingosine Kinase 2 in Serum-dependent Regulation of Cell Proliferation and Apoptosis." Journal of Biological Chemistry 280, no. 43 (August 15, 2005): 36318–25. http://dx.doi.org/10.1074/jbc.m504507200.
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Sphingosine kinase (SPHK) 1 is implicated in the regulation of cell proliferation and anti-apoptotic processes by catalyzing the formation of an important bioactive messenger, sphingosine 1-phosphate. Unlike the proliferative action of SPHK1, another isozyme, SPHK2, has been shown to possess anti-proliferative or pro-apoptotic action. Molecular mechanisms of SPHK2 action, however, are largely unknown. The present studies were undertaken to characterize the N-terminal-extended form of SPHK2 (SPHK2-L) by comparing it with the originally reported form, SPHK2-S. Real-time quantitative PCR analysis revealed that SPHK2-L mRNA is the major form in several human cell lines and tissues. From sequence analyses it was concluded that SPHK2-L is a species-specific isoform that is expressed in human but not in mouse. At the protein level it has been demonstrated by immunoprecipitation studies that SPHK2-L is the major isoform in human hepatoma HepG2 cells. SPHK2-L, when expressed in human embryonic kidney (HEK) 293 cells, did not show any inhibition of DNA synthesis in the presence of serum, whereas it showed marked inhibition in the absence of serum. Moreover, serum deprivation resulted in the translocation of SPHK2-L into the nuclei. In addition, serum deprivation induced SPHK2-L expression in HEK293 cells. Furthermore, suppression of SPHK2 by small interfering RNA treatment prevented serum deprivation- or drug-induced apoptosis in HEK293 cells. Taken together, these results indicate that a major form of SPHK2 splice variant, SPHK2-L, in human cells does not inhibit DNA synthesis under normal conditions and that SPHK2-L accumulation in the nucleus induced by serum deprivation may be involved in the cessation of cell proliferation or apoptosis depending on the cell type.
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Radeke, Heinfried, Olga Arlt, Annika Ranglack, and Josef Pfeilschifter. "In dendritic cells Toll-like receptor-dependent induction of IL-12p70 is accompanied by a profound down regulation of sphingosine-1-phosphate lyase mRNA (P1348)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 207.3. http://dx.doi.org/10.4049/jimmunol.190.supp.207.3.
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Abstract Sphingosine-1-phosphate (S1P) is an immune modulator produced by sphingosine kinase (SphK)1 and SphK2 and dephosphorylated by two S1P phosphatases or irreversibly degraded by a lyase. We recently showed that Toll-like receptor (TLR)4-induced IL-12p70 is selectively counter regulated by SphK1 and extracellular S1P/S1PR1. Others demonstrated that specific SphK1-dependent binding of intracellular S1P to TRAF2 enhances TNF signaling. In an ongoing investigation to determine the influence of extra- and intracellular S1P on dendritic cell signaling our experiments revealed that activation of TLR4 by lipopolysaccharide dose and time dependently decreased S1P lyase mRNA expression of murine bone marrow-derived dendritic cells by up to 70%. This set of realtime PCR data was further confirmed by semi-quantitative RT-PCR using exon-specific primers for murine sgpl1. Systematic analysis with dose-optimized ligands of TLRs 1/2, 5, 2/6, 7/8 and TLR9 showed a differential pattern of S1P lyase down regulation with concomitant increase of intracellular S1P. Although S1P lyase defcient mice are immune compromised, we found that TLR-induced transient S1P lyase downregulation resulted in a TLR adaptor-dependent upregulation of IL-12p70, IL-23 and IL-6 expression on mRNA and protein level. Further experiments including cell compartment-specific quantification of S1P, hexadecenal and, possibly counter regulatory, sphingolipid enzymes are necessary to understand the role of sphingolipids in DC.
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Prakash, Hridayesh, Anja Lüth, Natalia Grinkina, Daniela Holzer, Raj Wadgaonkar, Alexis Perez Gonzalez, Elsa Anes, and Burkhard Kleuser. "Sphingosine Kinase-1 (SphK-1) Regulates Mycobacterium smegmatis Infection in Macrophages." PLoS ONE 5, no. 5 (May 17, 2010): e10657. http://dx.doi.org/10.1371/journal.pone.0010657.
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Gomez-Larrauri, Ana, Natalia Presa, Asier Dominguez-Herrera, Alberto Ouro, Miguel Trueba, and Antonio Gomez-Muñoz. "Role of bioactive sphingolipids in physiology and pathology." Essays in Biochemistry 64, no. 3 (June 24, 2020): 579–89. http://dx.doi.org/10.1042/ebc20190091.
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Abstract Sphingolipids are a class of complex lipids containing a backbone of sphingoid bases, namely the organic aliphatic amino alcohol sphingosine (Sph), that are essential constituents of eukaryotic cells. They were first described as major components of cell membrane architecture, but it is now well established that some sphingolipids are bioactive and can regulate key biological functions. These include cell growth and survival, cell differentiation, angiogenesis, autophagy, cell migration, or organogenesis. Furthermore, some bioactive sphingolipids are implicated in pathological processes including inflammation-associated illnesses such as atherosclerosis, rheumatoid arthritis, inflammatory bowel disease (namely Crohn’s disease and ulcerative colitis), type II diabetes, obesity, and cancer. A major sphingolipid metabolite is ceramide, which is the core of sphingolipid metabolism and can act as second messenger, especially when it is produced at the plasma membrane of cells. Ceramides promote cell cycle arrest and apoptosis. However, ceramide 1-phosphate (C1P), the product of ceramide kinase (CerK), and Sph 1-phosphate (S1P), which is generated by the action of Sph kinases (SphK), stimulate cell proliferation and inhibit apoptosis. Recently, C1P has been implicated in the spontaneous migration of cells from some types of cancer, and can enhance cell migration/invasion of malignant cells through interaction with a Gi protein-coupled receptor. In addition, CerK and SphK are implicated in inflammatory responses, some of which are associated with cancer progression and metastasis. Hence, targeting these sphingolipid kinases to inhibit C1P or S1P production, or blockade of their receptors might contribute to the development of novel therapeutic strategies to reduce metabolic alterations and disease.
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Yoshino, Osamu, Kaori Yamada-Nomoto, Kuniyuki Kano, Yosuke Ono, Mutsumi Kobayashi, Masami Ito, Satoshi Yoneda, et al. "Sphingosine 1 Phosphate (S1P) Increased IL-6 Expression and Cell Growth in Endometriotic Cells." Reproductive Sciences 26, no. 11 (February 19, 2019): 1460–67. http://dx.doi.org/10.1177/1933719119828112.
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Objects: There is growing evidence that sphingosine 1-phosphate (S1P) is involved in inflammatory diseases. As endometriosis is known as an inflammatory disease, we investigated the role of S1P system in the development of endometriosis. Methods: The expression of sphingosine kinase (SphK) 1 in endometriosis lesions was examined by immunohistochemistry. The cystic fluid of ovarian cysts/tumors were obtained to measure S1P concentrations. Endometriotic stromal cells (ESC) derived from endometrioma were used for in vitro experiments. Results: Sphingosine kinase 1 was detected in epithelium and stromal cells of endometriotic lesions. The mean S1P concentration in the cystic fluid of endometriomas was higher than that in nonendometriomas significantly (98.2 nM vs less than 1.5 nM, P < .01). Interleukin-1β (IL-1β) or transforming growth factor-β exhibited 2.7-fold and 11.5-fold increase in SphK1 messenger RNA (mRNA) expression in ESC, respectively ( P < .01). Higher dose of S1P (125nM) increased the cell number of ESC by 20%, and low dose of S1P (1.25 nM and 12.5 nM) induced IL-6 mRNA production and IL-6 secretion by ESC dose-dependently. JTE013, an antagonist for S1PR2, partially suppressed IL-6 induction by S1P ( P < .05). JTE013 and VPC23019, an antagonist for S1PR1 and S1PR3, suppressed the ESC proliferation induced by S1P. Conclusion: The present study for the first time proved that the SphK-S1P-S1PR axis play a role of accelerating inflammation and growth of endometriotic cells.
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Vyas, Vibhuti, Charles R. Ashby, and Sandra E. Reznik. "Sphingosine Kinase: A Novel Putative Target for the Prevention of Infection-Triggered Preterm Birth." Obstetrics and Gynecology International 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/302952.
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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.
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Raymond, Marie-Noëlle, Christine Bole-Feysot, Yoshiko Banno, Zahra Tanfin, and Philippe Robin. "Endothelin-1 Inhibits Apoptosis through a Sphingosine Kinase 1-Dependent Mechanism in Uterine Leiomyoma ELT3 Cells." Endocrinology 147, no. 12 (December 1, 2006): 5873–82. http://dx.doi.org/10.1210/en.2006-0291.
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Uterine leiomyomas, or fibroids, are the most common tumors of the myometrium. The ELT3 cell line, derived from Eker rat leiomyoma, has been successfully used as a model for the study of leiomyomas. We have demonstrated previously the potent mitogenic properties of the peptidic hormone endothelin (ET)-1 in this cell line. Here we investigated the antiapoptotic effect of ET-1 in ELT3 cells. We found that 1) serum starvation of ELT3 cells induced an apoptotic process characterized by cytochrome c release from mitochondria, caspase-3/7 activation, nuclei condensation and DNA fragmentation; 2) ET-1 prevented the apoptotic process; and 3) this effect of ET-1 was fully reproduced by ETB agonists. In contrast, no antiapoptotic effect of ET-1 was observed in normal myometrial cells. A pharmacological approach showed that the effect of ET-1 on caspase-3/7 activation in ELT3 cells was not dependent on phosphatidylinositol 3-kinase, ERK1/2, or phospholipase D activities. However, inhibitors of sphingosine kinase-1 (SphK1), dimethylsphingosine and threo-dihydrosphingosine, reduced the effect of ET-1 by about 50%. Identical results were obtained when SphK1 expression was down-regulated in ELT3 cells transfected with SphK1 small interfering RNA. Furthermore, serum starvation induced a decrease in SphK1 activity that was prevented by ET-1 without affecting the level of SphK1 protein expression. Finally, sphingosine 1-phosphate, the product of SphK activity, was as efficient as ET-1 in inhibiting serum starvation-induced caspase-3/7 activation. Together, these results demonstrate that ET-1 possesses a potent antiapoptotic effect in ELT3 cells that involves sphingolipid metabolism through the activation of SphK1.
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Han, Hengmin, Seon-Ok Lee, Yinzhu Xu, Jung-Eun Kim, and Hyo-Jeong Lee. "SPHK/HIF-1α Signaling Pathway Has a Critical Role in Chrysin-Induced Anticancer Activity in Hypoxia-Induced PC-3 Cells." Cells 11, no. 18 (September 7, 2022): 2787. http://dx.doi.org/10.3390/cells11182787.
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Hypoxia, a typical feature of locally advanced solid tumors including prostate cancer, is a critical contributor to tumor progression and causes resistance to therapy. In this study, we investigated the effects of chrysin on tumor progression in hypoxic PC-3 cells. Chrysin exerted a significant inhibitory effect on 3D cell growth under normoxic and hypoxic conditions. It also decreased the hypoxia-induced vasculogenic mimicry and attenuated the expression of HIF-1α and VE-cadherin. Chrysin inhibited HIF-1α accumulation in a concentration- and time-dependent manner in hypoxic PC-3 cells, while also suppressing the expression of HIF-1α by inhibiting SPHK-1 in both CoCl2 and hypoxic PC-3 cells. At high concentrations of chrysin, there was a greater increase in apoptosis in the hypoxic cells compared to that in normoxic cells, which was accompanied by sub-G1 phase arrest. Chrysin-induced apoptosis inhibited VEGF and Bcl-2 and induced the cleavage of PARP and caspase-3. SPHK-1 knockdown induced apoptosis and inhibited epithelial–mesenchymal transition. Consistent with the in vitro data, 50 mg/kg of chrysin suppressed the tumor growth of PC-3 xenografts by 80.4% compared to that in the untreated control group. The immunohistochemistry of tumor tissues revealed decreased Ki-67, HIF-1α, and VEGF expression in the chrysin-treated group compared to an untreated control. Western blotting data for tumor tissues showed that chrysin treatment decreased SPHK-1, HIF-1α, and PARP expression while inducing caspase-3 cleavage. Overall, our findings suggest that chrysin exerts anti-tumor activity by inhibiting SPHK-1/HIF-1α signaling and thus represents a potent chemotherapeutic agent for hypoxia, which promotes cancer progression and is related to poor prognoses in prostate cancer patients.
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Hsu, Chia-Lin, and Paul Bryce. "IL-33 expression by mast cells is regulated by a Sphk-calcium-NFAT dependent pathway (117.5)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 117.5. http://dx.doi.org/10.4049/jimmunol.186.supp.117.5.
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Abstract IL-33 is an IL-1 family cytokine that can act extracellularly via its receptor, T1/ST2 or intracellularly. Functionally, it promotes Th2-associated immunity by enhancing several cell type activation and survival. However, the regulation of IL-33 expression is still unclear. Previously, we showed that basal expression of IL-33 in mast cells was upregulated upon IgE activation. Ca2+ mobilization was sufficient and necessary to enhance IL-33 expression in mast cells. We wanted to further investigate the pathway that drives IL-33 expression. Two major Ca2+-dependent pathways induced in mast cells are inositol trisphosphate (IP3) bound to its receptor, IP3R, and sphingosine kinase 1/2 (Sphk1/2) generated sphingosine-1-phosphate (S1P). PI3K is the upstream regulator for Sphk1. Here, we demonstrate that inhibition of PI3K and Sphk activity decreases IL-33 expression via IgE activation while ionomycin stimulation, which bypasses the inhibition, restores IL-33 expression. Interruption of NFAT and calcineurin interaction, which is downstream of Ca2+ mobilization, also decreases IL-33 expression and ionomycin can not restore it. Blocking of IP3R or NF-kB does not influence IL-33 expression but inhibits another IL-1 family cytokine, IL-1b. In summary, IL-33 is upregulated upon cross-linking of IgE receptors on mast cells and expression is dependent on Ca2+ mobilization and regulated by a PI3K-Sphk1-NFAT pathway.
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Motyl, Joanna A., Joanna B. Strosznajder, Agnieszka Wencel, and Robert P. Strosznajder. "Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease." International Journal of Molecular Sciences 22, no. 12 (June 11, 2021): 6277. http://dx.doi.org/10.3390/ijms22126277.
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Molecular studies have provided increasing evidence that Parkinson’s disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function—e.g., sphingosine-1-phosphate (S1P) and ceramide—is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the “sphingolipid biostat” favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P—a potent lipid mediator regulating cell fate and inflammatory response—making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD.
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Hengst, Jeremy A., Asvelt J. Nduwumwami, and Jong K. Yun. "Regulatory Role of Sphingosine-1-Phosphate and C16:0 Ceramide, in Immunogenic Cell Death of Colon Cancer Cells Induced by Bak/Bax-Activation." Cancers 14, no. 21 (October 22, 2022): 5182. http://dx.doi.org/10.3390/cancers14215182.
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We recently identified the sphingosine kinases (SphK1/2) as key intracellular regulators of immunogenic cell death (ICD) in colorectal cancer (CRC) cells. To better understand the mechanism by which SphK inhibition enhances ICD, we focused on the intracellular signaling pathways leading to cell surface exposure of calreticulin (ectoCRT). Herein, we demonstrate that ABT-263 and AZD-5991, inhibitors of Bcl-2/Bcl-XL and Mcl-1, respectively, induce the production of ectoCRT, indicative of ICD. Inhibition of SphK1 significantly enhanced ABT/AZD-induced ectoCRT production, in a caspase 8-dependent manner. Mechanistically, we demonstrate that ABT/AZD-induced Bak/Bax activation stimulates pro-survival SphK1/sphingosine-1-phosphate (S1P) signaling, which attenuates ectoCRT production. Additionally, we identified a regulatory role for ceramide synthase 6 (CerS6)/C16:0 ceramide in transporting of ectoCRT to the cell surface. Together, these results indicate that the sphingolipid metabolic regulators of the sphingolipid rheostat, S1P and C16:0 ceramide, influence survival/death decisions of CRC cells in response to ICD-inducing chemotherapeutic agents. Importantly, SphK1, which produces S1P, is a stress-responsive pro-survival lipid kinase that suppresses ICD. While ceramide, produced by the inhibition of SphK1 is required for production of the cell surface marker of ICD, ectoCRT. Thus, inhibition of SphK1 represents a means to enhance the therapeutic efficacy of ICD-inducing agents.
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Fu, P., PV Usatyuk, DL Ebenezer, and V. Natarajan. "ID: 111: THE S1P TRANSPORTER, SPNS2, MEDIATES HGF-INDUCED LAMELLIPODIA FORMATION AND MIGRATION OF HUMAN LUNG ENDOTHELIAL CELLS." Journal of Investigative Medicine 64, no. 4 (March 22, 2016): 964.2–965. http://dx.doi.org/10.1136/jim-2016-000120.109.
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RationaleWe have demonstrated earlier that HGF-induced lamellipodia formation in human lung microvascular endothelial cells (HLMVECs) was through c-Met receptor tyrosine kinase and PI3 kinase/Akt signal transduction. Here, we show that HGF-mediated lamellipodia formation is dependent on intracellular S1P generation mediated by sphingosine kinase 1 (SphK1), the S1P transporter, Spns2 and S1P1 in HLMVECs.MethodsHLMVECs were treated with HGF (20 ng/ml) for different time points. Lamellipodia were detected after HGF treatment by immunofluorescent staining of Spns2, cortactin and actin in lamellipodia, and lamellipodia were quantified by measuring cell periphery fluorescence intensity. Pearson's correlation coefficient was used to statistically quantify co-localization of proteins in lamellipodia. Endogenous SphK activity was blocked by SphK1 specific inhibitor PF-543, and expression of SphK1 in cells was down-regulated by siRNA. Cellular S1P levels were quantified by mass spectrometry.ResultsHGF stimulated phosphorylation of SphK1, and its localization to lamellipodia of HLMVECs. Down-regulation of SphK1, but not SphK2, with siRNA or inhibition of SphK1 with PF-543 (1–5 µM) attenuated HGF-induced lamellipodia formation in HLMVECs. The HGF-mediated phosphorylation of SphK1 and its localization in lamellipodia was dependent on PI3K/Akt and ERK1/2 signaling apthways. HGF increased S1P levels in HLMVECs, which was blocked by inhibition of SphK1 with PF-543. Further, HGF induced serine phosphorylation and translocation of Spns2, the S1P transporter, to lamellipodia, which was Akt dependent. The HGF-induced lamellipodia formation in HLMVECs was blocked by down-regulation of Spns2, suggesting extracellular action of S1P in lamellipodia formation. Down-regulation of S1P1, but not S1P2 or S1P3, with siRNA attenuated HGF-induced lamellipodia formation. Further, HGF stimulation enhanced association of Spns2 with S1P1 and blocking SphK1 activty with PF-543 attenuated the association between Spns2 and S1P1. Additionally, HGF-induced migration of HLMVECs was attenuated by down-regulation of Spns2.ConclusionThese results suggest that HGF/c-Met mediated lamellipodia formation and motility is dependent on intracellular generation of S1P via activation and localization of SphK1 to cell periphery and Spns2 mediated transport of S1P to outside for signaling via S1P1 in HLMVECs. This work was supported by NIH/HLBI P01 HL98050 to VN.
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Lai, Wen-Qi, W. S. Fred Wong, and Bernard P. Leung. "Sphingosine kinase and sphingosine 1-phosphate in asthma." Bioscience Reports 31, no. 2 (November 23, 2010): 145–50. http://dx.doi.org/10.1042/bsr20100087.
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Sphingolipids are amphiphatic molecules ubiquitously expressed in all eukaryotic cell membranes. Initially characterized as structural components of cell membranes, sphingolipids have emerged as sources of important signalling molecules over the past decade. Sphingolipid metabolites, such as ceramide and S1P (sphingosine 1-phosphate), have been demonstrated to have roles as potent bioactive messengers involved in cell differentiation, proliferation, apoptosis, migration and angiogenesis. The importance of SphK (sphingosine kinase) and S1P in inflammation has been demonstrated extensively. The prevalence of asthma is increasing in many developed nations. Consequently, there is an urgent need for the development of new agents for the treatment of asthma, especially for patients who respond poorly to conventional therapy. Recent studies have demonstrated the important role of SphK and S1P in the development of asthma by regulating pro-inflammatory responses. These novel pathways represent exciting potential therapeutic targets in the treatment of asthma and are described in the present review.