scholarly journals Role of sphingosine kinase‐1 in paracrine/transcellular angiogenesis and lymphangiogenesis in vitro

2010 ◽  
Vol 24 (8) ◽  
pp. 2727-2738 ◽  
Author(s):  
Viviana Anelli ◽  
Christopher R. Gault ◽  
Ashley J. Snider ◽  
Lina M. Obeid
Keyword(s):  
Sphingosine Kinase ◽  
Sphingosine Kinase 1

Role and Regulation Of Erythrocyte Sphingosine Kinase 1 Activity In Normal and Sickle Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 315-315
Author(s):  
Sun Kaiqi ◽  
Yujin Zhang ◽  
Vladimir Berka ◽  
Rodney E. Kellems ◽  
Ah-lim Tsai ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sphingosine Kinase ◽  
In Vitro Studies ◽  
Allosteric Modulator ◽  
Sphingosine Kinase 1 ◽  
Cell Disease ◽  
Deficient Mice

Abstract Sickle Cell Disease (SCD) is a devastating genetic disorder attacking red blood cells (RBCs) and affecting millions of humans worldwide. The Glu/Val mutation in the sixth amino acid of β-globin leads to the polymerization of deoxygenated sickle hemoglobin and subsequent sickling, which initiates the disease. Although SCD has been studied for more than a century, factors that contribute to sickling remain unclear. Our lab recently conducted non-biased metabolomic screening and identified that the levels of a small signaling lipid, sphingosine 1-phosphate (S1P), were dramatically increased in SCD transgenic (Tg) mice and patients. Although S1P is enriched and stored in erythrocytes, the role of S1P in normal and sickle erythrocytes remains unknown. Here we revealed that elevated S1P is a previously unrecognized allosteric modulator collaboratively working with 2, 3-bisiphosphoglycerate (2, 3-BPG) to facilitate oxygen release and thereby triggers sickling. Subsequently, we found that the enzymatic activity of sphingosine kinase 1 (Sphk1), which is the only enzyme producing S1P inside red blood cell (RBCs), is significantly elevated in SCD Tg mice and patients. Intriguingly, we found that hypoxia condition significantly increases Sphk1 activity and decreases hemoglobin oxygen (O2) binding affinity in WT mice but not in Sphk1–deficient mice. In a view of 1) our finding that SphK1 activity is induced by hypoxia; 2) our recent finding that excessive adenosine signaling through the A2B adenosine receptor (ADORA2B) promoting sickling by induction 2,3-BPG (Zhang, et al, Nature Medicine, 2011) and 3) the fact that adenosine is a signaling nucleoside that elicits many physiological effects via its receptors under hypoxic conditions, we hypothesized that adenosine functions via its receptors regulating Sphk1 activity and S1P production in erythrocytes. To test this hypothesis, we conducted both pharmacological and genetic studies. First, we found that adenosine directly induces SphK1 activities in cultured primary mouse and human normal erythrocytes. Next, we found that genetic deletion or inhibition of ADORA2B significantly reduces adenosine-induced SphK1 activities in cultured RBCs. Extending in vitro studies to in vivo experiments, we showed that excess circulating adenosine in adenosine deaminase (ADA, adenosine degrading enzyme)-deficient mice leads to significantly increased erythrocyte SphK1 activities. Similar to in vitro studies, we further found that specific deletion of ADORA2B in ado-/-(i.e ado-/-/adora2b-/- double deficient mice) abolishes excess adenosine-induced SphK1 activities in RBCs. Mechanistically, we further revealed that extralcellular signal regulated kinase (ERK) and protein kinase A (PKA) function downstream of ADORA2B underlying adenosine-induced erythrocyte Sphk1 activity. Overall, our studies demonstrate that 1) S1P is an allosteric modulator to induce O2 release and trigger sickling; 2) elevated adenosine functions via ADORA2B coupled with PKA and ERK signaling network responsible for elevated erythrocyte SphK1 activities and S1P production. Therefore, our findings reveal a previously unrecognized role of SphK1-S1P in erythrocyte physiology and novel mechanisms regulating its activities, add a new insight to the pathophysiology of SCD and open up new therapies for the disease. Disclosures: No relevant conflicts of interest to declare.

Role of sphingosine kinase 1 (SphK1) on cetuximab resistance in colorectal cancer models.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13509-e13509
Author(s):  
Roberto Bianco ◽  
Roberta Rosa ◽  
Lucia Nappi ◽  
Luigi Formisano ◽  
Vincenzo Damiano ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Anticancer Agents ◽  
Acquired Resistance ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Mutational Status ◽  
Resistant Cells

e13509 Background: Although EGFR inhibitors, such as the mAb cetuximab, represent an effective strategy in colorectal cancer (CRC), the clinical use of these agents is limited by intrinsic or acquired resistance. Alterations in the ‘sphingolipid rheostat’, or the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P), due to overactivation of sphingosine kinase 1 (SphK1), have been involved in the regulation of resistance to anticancer agents. Since some studies described cross-talks between SphK1 and EGFR-dependent signalling pathways, we investigated the contribution of SphK1 to cetuximab resistance in CRC models. Methods: We used CRC cell lines with both intrinsic or acquired resistance to cetuximab. In these models, we analyzed SphK1 expression/activation by using different tools, including the available drug fingolimod (FTY720), both in vitro and in vivo. We confirmed our data through a tissue microarray (TMA)-based analysis on CRC tissues. Results: SphK1 is overexpressed in CRC cells resistant to cetuximab. Higher doses of N,N-dimethylsphingosine (DMS), a potent competitive inhibitor of SphK1, are needed to achieve complete enzyme saturation and survival inhibition in resistant cells. Moreover, ceramide induces apoptosis less efficiently in resistant than in sensitive cells, consistently with the idea that increased SphK1 levels mediate S1P synthesis by ceramide in resistant cells. SphK1 contribution to resistance is supported by the demonstration that SphK1 inhibition by DMS or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in wild-type cells confers resistance. Re-sensitization to cetuximab is observed after treatment with fingolimod, a S1P receptor inhibitor, both in vitro and in nude mice xenografted with CRC cells. Finally, a TMA-based analysis on CRC tissues revealed that SphK1 expression is related to K-Ras mutational status, a well-known determinant of cetuximab resistance. Conclusions: Our data could clarify the role of SphK1 in the onset of resistance to cetuximab, thus suggesting SphK1 inhibition as a part of novel targeting strategies for resistant cancer patients.

scholarly journals Silencing of Sphingosine kinase 1 Affects Maturation Pathways in Mouse Neonatal Cardiomyocytes

2021 ◽  
Vol 22 (7) ◽  
pp. 3616
Author(s):  
Ewelina Jozefczuk ◽  
Piotr Szczepaniak ◽  
Tomasz Jan Guzik ◽  
Mateusz Siedlinski
Keyword(s):  
Cardiac Development ◽  
Glycogen Synthase ◽  
Sphingosine Kinase ◽  
Negative Control ◽  
Neonatal Mouse ◽  
Sphingosine Kinase 1 ◽  
Postnatal Maturation ◽  
Neonatal Cardiomyocytes ◽  
Pathological Cardiac Hypertrophy

Sphingosine kinase-1 (Sphk1) and its product, sphingosine-1-phosphate (S1P) are important regulators of cardiac growth and function. Numerous studies have reported that Sphk1/S1P signaling is essential for embryonic cardiac development and promotes pathological cardiac hypertrophy in adulthood. However, no studies have addressed the role of Sphk1 in postnatal cardiomyocyte (CM) development so far. The present study aimed to assess the molecular mechanism(s) by which Sphk1 silencing might influence CMs development and hypertrophy in vitro. Neonatal mouse CMs were transfected with siRNA against Sphk1 or negative control, and subsequently treated with 1 µM angiotensin II (AngII) or a control buffer for 24 h. The results of RNASeq analysis revealed that diminished expression of Sphk1 significantly accelerated neonatal CM maturation by inhibiting cell proliferation and inducing developmental pathways in the stress (AngII-induced) conditions. Importantly, similar effects were observed in the control conditions. Enhanced maturation of Sphk1-lacking CMs was further confirmed by the upregulation of the physiological hypertrophy-related signaling pathway involving Akt and downstream glycogen synthase kinase 3 beta (Gsk3β) downregulation. In summary, we demonstrated that the Sphk1 silencing in neonatal mouse CMs facilitated their postnatal maturation in both physiological and stress conditions.

Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-216469
Author(s):  
Alison W Ha ◽  
Tao Bai ◽  
David L Ebenezer ◽  
Tanvi Sethi ◽  
Tara Sudhadevi ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lysyl Oxidase ◽  
Critical Role ◽  
Sphingosine Kinase ◽  
In Vivo Studies ◽  
Sphingosine Kinase 1 ◽  
Neonatal Lung ◽  
Neonatal Lung Injury

IntroductionNeonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD.MethodThe enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1−/− and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs).ResultsBoth SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1−/− and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P1) and STAT3 reduced LOX expression.ConclusionHO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P1 and STAT3 in lung endothelium.

Islet Co-Expression of CD133 and ABCB5 in Human Retinoblastoma Specimens

2021 ◽  
Author(s):  
Marco Zschoche ◽  
Sergej Skosyrski ◽  
Neele Babst ◽  
Mahdy Ranjbar ◽  
Felix Rommel ◽  
...  
Keyword(s):  
Treatment Resistance ◽  
Sphingosine Kinase ◽  
Immunohistochemical Analysis ◽  
Pcr Analysis ◽  
Sphingosine Kinase 1 ◽  
Rt Pcr ◽  
Beam Radiation ◽  
Sphingosine Kinase 2 ◽  
Human Retinoblastoma

Abstract Background The role of CD133 und ABCB5 is discussed in treatment resistance in several types of cancer. The objective of this study was to evaluate whether CD133+/ABCB5+ colocalization differs in untreated, in beam radiation treated, and in chemotherapy treated retinoblastoma specimens. Additionally, CD133, ABCB5, sphingosine kinase 1, and sphingosine kinase 2 gene expression was analyzed in WERI-RB1 (WERI RB1) and etoposide-resistant WERI RB1 subclones (WERI ETOR). Methods Active human untreated retinoblastoma specimens (n = 12), active human retinoblastoma specimens pretreated with beam radiation before enucleation (n = 8), and active human retinoblastoma specimens pretreated with chemotherapy before enucleation (n = 7) were investigated for localization and expression of CD133 and ABCB5 by immunohistochemistry. Only specimens with IIRC D, but not E, were included in this study. Furthermore, WERI RB1 and WERI ETOR cell lines were analyzed for CD133, ABCB5, sphingosine kinase 1, and sphingosine kinase 2 by the real-time polymerase chain reaction (RT-PCR). Results Immunohistochemical analysis revealed the same amount of CD133+/ABCB5+ colocalization islets in untreated and treated human retinoblastoma specimens. Quantitative RT-PCR analysis showed a statistically significant upregulation of CD133 in WERI ETOR (p = 0.002). No ABCB5 expression was detected in WERI RB1 and WERI ETOR. On the other hand, SPHK1 (p = 0.0027) and SPHK2 (p = 0.017) showed significant downregulation in WERI ETOR compared to WERI RB1. Conclusions CD133+/ABCB5+ co-localization islets were noted in untreated and treated human retinoblastoma specimens. Therefore, we assume that CD133+/ABCB5+ islets might play a role in retinoblastoma genesis, but not in retinoblastoma treatment resistance.

scholarly journals Detrimental role of sphingosine kinase 1 in kidney damage in DOCA-salt hypertensive model: evidence from knockout mice

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Bingqing Lyu ◽  
Weili Wang ◽  
Xin-Ying Ji ◽  
Joseph K. Ritter ◽  
Ningjun Li
Keyword(s):  
Knockout Mice ◽  
Sphingosine Kinase ◽  
Kidney Damage ◽  
Sphingosine Kinase 1 ◽  
Model Evidence

scholarly journals Role of sphingosine kinase 1 and sphingosine‐1‐phosphate in CD40 signaling and IgE class switching

2014 ◽  
Vol 28 (10) ◽  
pp. 4347-4358 ◽  
Author(s):  
Eugene Y. Kim ◽  
Jamie L. Sturgill ◽  
Nitai C. Hait ◽  
Dorit Avni ◽  
Evelyn C. Valencia ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Class Switching ◽  
Sphingosine 1 Phosphate

scholarly journals Role of Sphingosine Kinase 1 and S1P Transporter Spns2 in HGF-mediated Lamellipodia Formation in Lung Endothelium

2016 ◽  
Vol 291 (53) ◽  
pp. 27187-27203 ◽  
Author(s):  
Panfeng Fu ◽  
David L. Ebenezer ◽  
Evgeny V. Berdyshev ◽  
Irina A. Bronova ◽  
Mark Shaaya ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Lung Endothelium ◽  
Lamellipodia Formation

scholarly journals Sphingosine Kinase 1 Is Required for Mesothelioma Cell Proliferation: Role of Histone Acetylation

PLoS ONE ◽  
2012 ◽  
Vol 7 (9) ◽  
pp. e45330 ◽  
Author(s):  
Satish Kalari ◽  
Nagabhushan Moolky ◽  
Srikanth Pendyala ◽  
Evgeny V. Berdyshev ◽  
Cleo Rolle ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Histone Acetylation ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Mesothelioma Cell
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