Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular application of lysophosphatidic acid (LPA) elevated intracellular Ca(2+) concentration ([Ca(2+)](i)) in human SH-SY5Y neuroblastoma cells. The maximal response to LPA occurred between 0. 1 and 1 microM, at which point [Ca(2+)](i) was increased by approx. 500 nM. This increase was of similar magnitude to that caused by the muscarinic acetylcholine receptor agonist methacholine (MCh), although the initial rate of release by LPA was slower. Both LPA and MCh released Ca(2+) from intracellular stores, as assessed by inhibition of their effects by thapsigargin, a blocker of endoplasmic reticular Ca(2+) uptake, and by the persistence of their action in nominally Ca(2+)-free extracellular medium. Similarly, both agonists appeared to stimulate store-refilling Ca(2+) entry. MCh produced a marked elevation in cellular Ins(1,4,5)P(3) and stimulated [(3)H]InsP accumulation in the presence of Li(+). In contrast, LPA failed to stimulate detectable phosphoinositide turnover. Chronic down-regulation of Ins(1,4,5)P(3) receptor (InsP(3)R) proteins with MCh did not affect Ca(2+) responses to LPA. In addition, heparin, a competitive antagonist of InsP(3)Rs, blocked Ca(2+)-mobilization in permeabilized SH-SY5Y cells in response to MCh or exogenously added Ins(1,4,5)P(3), but failed to inhibit Ca(2+)-release induced by LPA. Elevation of [Ca(2+)](i) elicited by LPA was blocked by guanosine 5'-[beta-thio]-diphosphate, indicating that this agonist acts via a G-protein-coupled receptor. However, pertussis toxin was without effect on LPA-evoked [Ca(2+)](i) responses, suggesting that G(i/o)-proteins were not involved. In the absence of extracellular Ca(2+), N,N-dimethylsphingosine (DMS, 30 microM), a competitive inhibitor of sphingosine kinase, blocked LPA-induced Ca(2+) responses by almost 90%. In addition, MCh-induced Ca(2+) responses were also diminished by the addition of DMS, although to a lesser extent than with LPA. We conclude that LPA mobilizes intracellular Ca(2+)-stores in SH-SY5Y cells independently of the generation and action of Ins(1,4,5)P(3). Furthermore, the Ca(2+)-response to LPA appears to be dependent on sphingosine kinase activation and the potential generation of the putative second messenger sphingosine 1-phosphate.
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PMID:Lysophosphatidic acid-mediated Ca2+ mobilization in human SH-SY5Y neuroblastoma cells is independent of phosphoinositide signalling, but dependent on sphingosine kinase activation. 1049 10

There is increasing evidence that sphingolipids are involved in cell survival, differentiation or commitment to death. The effect of different sphingolipids and inhibitors of mitogen-activated protein kinase (MAPK) cascade on SH-SY5Y neuroblastoma cell death has been studied. Permeant ceramide analogues C2-Cer, C8-Cer, and C8-Cer-1-phosphate, but not dihydro C2-Cer induce apoptosis, as shown by Hoechst staining. Inhibition of ceramidase and sphingosine kinase, as well as incubation with sphingosine, decreases cell viability, measured as 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide reduction, whereas addition of sphingosine-1-phosphate increases proliferation. Both PD98059 (MAPKK inhibitor) and SB202190 (p38 MAPK inhibitor) decreased viability, but only SB202190 abolished the effect of ceramide. These results suggest that in SH-SY5Y neuroblastoma cells, death is signalled by increases in ceramide, ceramide-phosphate or sphingosine content through p38 MAPK pathway while survival requires MAPK and high sphingosine-1-phosphate/ceramide ratio.
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PMID:Sphingomyelinase metabolites control survival and apoptotic death in SH-SY5Y neuroblastoma cells. 1080 17

The sphingosine kinase inhibitor, dimethylsphingosine, is an important tool for investigating intracellular effects of the putative second messenger compound, sphingosine 1-phosphate. However, the specificity of action of dimethylsphingosine has not been fully investigated. In human SH-SY5Y neuroblastoma cells, dimethylsphingosine (30 microM), produced a 25-fold increase in the EC(50) for methacholine-induced Ca(2+) mobilisation, and reduced the maximum response by 57+/-5%, suggesting the involvement of sphingosine 1-phosphate production in the Ca(2+) signal. However, dimethylsphingosine also inhibited [3H]N-methylscopolamine binding to whole SH-SY5Y cells and reduced methacholine-induced phosphoinositide turnover. Thus, this compound must be used with caution when investigating the role of sphingosine kinase in G-protein coupled receptor-mediated Ca(2+) mobilisation responses.
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PMID:Effect of dimethylsphingosine on muscarinic M(3) receptor signalling in SH-SY5Y cells. 1094 Mar 57

Lysophosphatidic acid (LPA)-mediated Ca(2+) mobilization in human SH-SY5Y neuroblastoma cells does not involve either inositol 1,4, 5-trisphosphate (Ins(1,4,5)P(3))- or ryanodine-receptor pathways, but is sensitive to inhibitors of sphingosine kinase. This present study identifies Edg-4 as the receptor subtype involved and investigates the presence of a Ca(2+) signaling cascade based upon the lipid second messenger molecule, sphingosine 1-phosphate. Both LPA and direct G-protein activation increase [(3)H]sphingosine 1-phosphate levels in SH-SY5Y cells. Measurements of (45)Ca(2+) release in premeabilized SH-SY5Y cells indicates that sphingosine 1-phosphate, sphingosine, and sphingosylphosphorylcholine, but not N-acetylsphingosine are capable of mobilizing intracellular Ca(2+). Furthermore, the effect of sphingosine was attenuated by the sphingosine kinase inhibitor dimethylsphingosine, or removal of ATP. Confocal microscopy demonstrated that LPA stimulated intracellular Ca(2+) "puffs," which resulted from an interaction between the sphingolipid Ca(2+) release pathway and Ins(1,4,5)P(3) receptors. Down-regulation of Ins(1,4,5)P(3) receptors uncovered a Ca(2+) response to LPA, which was manifest as a progressive increase in global cellular Ca(2+) with no discernible foci. We suggest that activation of an LPA-sensitive Edg-4 receptor solely utilizes the production of intracellular sphingosine 1-phosphate to stimulate Ca(2+) mobilization in SH-SY5Y cells. Unlike traditional Ca(2+) release processes, this novel pathway does not require the progressive recruitment of elementary Ca(2+) events.
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PMID:Lysophosphatidic acid-induced Ca2+ mobilization requires intracellular sphingosine 1-phosphate production. Potential involvement of endogenous EDG-4 receptors. 1095 27

The effects of different calcium-mobilizing agents on cell death were characterized in NG108-15 neuroblastoma x glioma hybrid cells. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) increased the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and caused cell death. Thapsigargin (TG) not only increased the [Ca(2+)](i) and caused cell death but also induced neurite outgrowth via activation of phospholipase A(2) and cytochrome P450 epoxygenase. In contrast, bradykinin increased the [Ca(2+)](i), but had no effect on cell morphology or cell death. Cell death occurred by two different mechanisms, one of which was caspase-3-dependent and the other caspase-3-independent. Caspase-3 activation was Ca(2+)-dependent, whereas neurite outgrowth was Ca(2+)-independent. TG- or FCCP-induced caspase-3 activation occurred at the same time, but the cell death induced by TG was delayed. TG treatment did not enhance the generation of nitric oxide or cAMP or secretion of glial-derived neurotrophic factor or neurotrophin-3, but activated sphingosine kinase. Furthermore, inhibition of sphingosine kinase accelerated TG-induced cell death, and exogenous sphingosine 1-phosphate (S1P) protected cells from FCCP-induced cell death by about 60%. These results indicate that, in these cells, depletion of intracellular nonmitochondrial or mitochondrial Ca(2+) stores causes cell death, that TG activates phospholipase A(2) and sphingosine kinase, and that arachidonic acid induces neurite outgrowth, whereas S1P delays cell death.
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PMID:Distinct effects of different calcium-mobilizing agents on cell death in NG108-15 neuroblastoma X glioma cells. 1185 28

Activation of sphingosine kinase (SPHK), thereby increasing cellular levels of sphingosine 1-phosphate (S1P), may be involved in a variety of intracellular responses including Ca(2+) signaling. This study uses mammalian SPHK1a, tagged with enhanced green fluorescent protein (eGFP), to examine whether translocation of this enzyme is linked with Ca(2+)-mobilizing responses. Real-time confocal imaging of SPHK1a-eGFP in human SH-SY5Y neuroblastoma cells visualized a relocation of the enzyme from the cytosol to the plasma membrane in response to Ca(2+)-mobilizing stimuli (muscarinic M(3)- or lysophosphatidic acid receptor activation, and thapsigargin-mediated store release). This redistribution was preceded by a transient increase in cytosolic SPHK1a-eGFP levels due to liberation of SPHK from localized higher intensity regions. Translocation was dependent on Ca(2+) mobilization from intracellular stores, and was prevented by pretreatment with the Ca(2+)/calmodulin inhibitor W-7, but not W-5 or KN-62. In functional studies, pretreatment with W-7 lowered basal and M(3)-receptor-mediated cellular S1P production. However, this pretreatment did not alter agonist-mediated Ca(2+) responses, and SPHK1a-eGFP activity itself appeared insensitive to Ca(2+)/calmodulin and W-7. These data suggest a role for Ca(2+)/calmodulin in controlling the subcellular distribution but not the activity of SPHK1a.
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PMID:Ca2+/calmodulin-dependent translocation of sphingosine kinase: role in plasma membrane relocation but not activation. 1253 Nov 88

The 7-oxasphingosine (1), 7-oxaceramide (2), the thio-oxaceramide 3, and N-methyloxaceramide 4 were synthesised from D-galactose via the building block 9. The apoptosis-inducing properties of 1-4 were compared to those of sphingosine (Sph) and ceramide (Cer) using a human neuroblastoma (SK-N-BE) and a murine-promyelocyte-derived (32d) cell line. There were no differences between 2-4 and Cer in terms of their effects on the viability of cells and their ability to trigger cell proliferation. However, in the presence of N,N-dimethylsphingosine, an inhibitor of sphingosine kinase (SPHK), Cer was more potent than thio-ceramide 3 in 32d cells, while thio-ceramide 3 was more potent and efficacious in SK-N-BE cells, where it showed an IC50 value of 3 nM compared to 100 nM for Cer. In both SK-N-BE and 32d cells, 7-oxasphingosine (1) and Sph were equally toxic, even in the presence of N,N-dimethylsphingosine.
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PMID:Synthesis of 7-oxasphingosine and -ceramide analogues and their evaluation in a model for apoptosis. 1719 16

We examined the role of sphingosine kinase-1 (SphK1), a critical regulator of the ceramide/sphingosine 1-phosphate (S1P) biostat, in the regulation of death and survival of SH-SY5Y neuroblastoma cells in response to amyloid beta (Abeta) peptide (25-35). Upon incubation with Abeta, SH-SY5Y cells displayed a marked down-regulation of SphK1 activity coupled with an increase in the ceramide/S1P ratio followed by cell death. This mechanism was redox-sensitive; N-acetylcysteine totally abrogated the down-regulation of SphK1 activity and strongly inhibited Abeta-induced cell death. SphK1 overexpression impaired the cytotoxicity of Abeta, whereas SphK1 silencing by RNA interference mimicked Abeta-induced cell death, thereby establishing a critical role for SphK1. We further demonstrated that SphK1 could mediate the well established cytoprotective action of insulin-like growth factor (IGF-I) against Abeta toxicity. A dominant-negative form of SphK1 or its pharmacological inhibition not only abrogated IGF-I-triggered stimulation of SphK1 but also hampered IGF-I protective effect. Similarly to IGF-I, the neuroprotective action of TGF-beta1 was also dependent on SphK1 activity; activation of SphK1 as well as cell survival were impeded by a dominant-negative form of SphK1. Taken together, these results provide the first illustration of SphK1 role as a critical regulator of death and survival of Abeta-treated cells.
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PMID:Critical role for sphingosine kinase-1 in regulating survival of neuroblastoma cells exposed to amyloid-beta peptide. 1752 81

RET, the receptor of glial cell line-derived neurotrophic factor (GDNF) family ligands, is important for the development of kidney and peripheral neurons. GDNF promotes survival and differentiation of neurons. Mutation of RET leads to the constitutive signal activation causing papillary thyroid carcinoma and multiple endocrine neoplasia type 2 (MEN2). In this study, we report that GDNF/RET signaling up-regulates sphingosine kinase (SPHK) enzyme activity, SPHK1 protein and SPHK1 message in TGW human neuroblastoma cells. Silencing of SPHK1 using siRNA inhibited GDNF-induced neurite formation, GAP43 expression, and cell growth, suggesting the important role of SPHK1 in GDNF signal transduction. Furthermore, NIH3T3 cells transfected with MEN2A type mutated RET but not c-RET demonstrated the up-regulation of SPHK activity, SPHK1 protein and SPHK1 message compared with NIH3T3 cells. The cell growth and anchorage-independent colony formation of MEN2A-NIH3T3 was inhibited with siRNA of SPHK1, while no effect of scramble siRNA was observed. These results suggest the oncogenic role of SPHK1 in MEN2A type tumor. Promoter analysis showed that activator protein 2 and specificity protein 1 binding motif of the 5' promoter region of SPHK1 gene is important for its induction by GDNF. Furthermore, we demonstrated that ERK1/2 and PI3 kinase are involved in GDNF-induced SPHK1 transcription by using specific inhibitors.
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PMID:RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis. 1755 48

Metabolism of sphingolipids into downstream lipid mediators followed by signaling modulates tumor microenvironment and the cancer cells to influence tumor progression. As such, sphingolipid signaling represents a novel way to modulate tumor biology. Neuroblastoma (NB), the most common extracranial solid tumor of childhood, is highly angiogenic and often displays poor prognosis. However, the role of sphingolipid mediators is not known in NB. We found that NB expresses high levels of sphingosine kinase-2, which is essential for the formation of sphingosine-1-phosphate (S1P). S1P induced VEGF expression in SK-N-AS NB cells. The effect occurred at the transcriptional level. Hypoxia in combination with S1P had a synergistic effect on VEGF expression. Strong correlation was detected between S1P receptor-2 (S1P(2)) and VEGF mRNAs in 11 different cell lines and 17 NB tissues. Blockade of S1P(2) with the selective antagonist JTE-013 significantly inhibited S1P-induced VEGF expression. Overexpression and knockdown of S1P(2) in SK-N-AS cells increased or inhibited S1P-induced VEGF secretion, respectively. Interestingly, JTE-013 significantly inhibited tumor growth, VEGF mRNA expression, and induced apoptosis in the NB tumor xenografts. Taken together, our data suggest that enhanced formation of sphingolipid mediator S1P in NB profoundly influences tumor microenvironment by inducing VEGF expression via S1P(2). Modulation of sphingolipid signaling by inhibiting S1P(2) may constitute a novel strategy to control NB.
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PMID:Sphingolipid modulation of angiogenic factor expression in neuroblastoma. 2157 49


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