Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Dopamine (DA) was shown to exert toxic effects on cultured neurons through autoxidation or oxidative deamination, followed by formation of highly reactive quinone compounds and superoxide radicals. In the present study, therefore, any involvement of Cu-Zn superoxide dismutase (SOD) in DA toxicity was evaluated by transfection of Cu-Zn SOD cDNA. The transient transfection of Cu-Zn SOD cDNA inhibited the DA-induced decrease of dopaminergic neuroblastoma cells. Moreover, Cu-Zn SOD cDNA-transfection significantly increased the glutathione (GSH) level when the cells were exposed to DA. However, such Cu-Zn SOD-overexpression failed to show any protective effects against hydrogen peroxide. The Cu-Zn SOD-overexpressing cells also showed significantly higher levels of GSH upon DA exposure than did the empty vector-transfected cells. The increase in the GSH level in response to hydrogen peroxide remained almost identical in empty vector-transfected or Cu-Zn SOD-overexpressed cells. The level of GSH in DA-treated Cu-Zn SOD-overexpressing cells was 2.5-fold higher than that increased by hydrogen peroxide exposure. The catechol structure of DA molecule is probably involved in the mechanism of increasing GSH level. Furthermore, the Cu-Zn SOD-overexpressing cells inhibited the activation of caspase-3 upon DA exposure. Therefore, Cu-Zn SOD overexpression may temporarily inhibit or delay DA autoxidation and consequently increase the GSH level, which then prevents the activation of apoptotic pathway and subsequent cell death.
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PMID:Overexpression of Cu-Zn superoxide dismutase protects neuroblastoma cells against dopamine cytotoxicity accompanied by increase in their glutathione level. 1294 44

Dopamine, which is suggested as a prominent etiological factor in several neuropsychiatric disorders such as Parkinson's disease and schizophrenia, demonstrates neurotoxic properties. In such dopamine-related diseases mitochondrial dysfunction has been reported. Dopamine oxidized metabolites were shown to inhibit the mitochondrial respiratory system both in vivo and in vitro. In the present study, we suggest an additional mechanism for dopamine toxicity, which involves mitochondrial complex I inhibition by dopamine. In human neuroblastoma SH-SY5Y cells dopamine induced a reduction in ATP concentrations, which was negatively correlated to intracellular dopamine levels (r = - 0.96, P = 0.012), and was already evident at non-toxic dopamine doses. In disrupted mitochondria dopamine inhibited complex I activity with IC50 = 11.87 +/- 1.45 microm or 8.12 +/- 0.75 microM in the presence of CoQ or ferricyanide, respectively, with no effect on complexes IV and V activities. The catechol moiety, but not the amine group, of dopamine is essential for complex I inhibition, as is indicated by comparing the inhibitory potential of functionally and structurally dopamine-related compounds. In line with the latter is the finding that chelatable FeCl2 prevented dopamine-induced inhibition of complex I. Monoamine oxidase A and B inhibitors, as well as the antioxidant butylated hydroxytoluene (BHT), did not prevent dopamine-induced inhibition, suggesting that dopamine oxidation was not involved in this process. The present study suggests that dopamine toxicity involves, or is initiated by, its interaction with the mitochondrial oxidative phosphorylation system. We further hypothesize that this interaction between dopamine and mitochondria is associated with mitochondrial dysfunction observed in dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease.
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PMID:Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders. 1513 Jul 72

Postsynaptic striatal neurodegeneration occurs through unknown mechanisms, but it is linked to high extracellular levels of synaptic dopamine. Dopamine-mediated cytotoxicity of striatal neurons occurs through two distinct pathways: autoxidation and the D1 dopamine receptor-linked signaling pathway. Here we investigated the mitogen-activated protein kinase (MAPK) signaling pathways activated upon the acute stimulation of D1 dopamine receptors. In SK-N-MC neuroblastoma cells, endogenously expressing D1 dopamine receptors, dopamine caused activation of phosphorylated (p-)ERK1/2 and of the stress-signaling kinases, p-JNK and p-p38 MAPK, in a time- and dose-dependent manner. Selective stimulation of D1 receptors with the agonist SKF R-38393 caused p-ERK1/2, but not p-JNK or p-p38 MAPK activation, in a manner sensitive to the receptor-selective antagonist SCH 23390, protein kinase A inhibition (KT5720), and MEK1/2 inhibition (U0126 or PD98059). Activation of ERK by D1 dopamine receptors resulted in oxidative stress and cytotoxicity. In cells transfected with a catalytically defective mutant of MEK1, the upstream ERK-specific kinase, both dopamine- and SKF R-38393-mediated cytotoxicity was markedly attenuated, confirming the participation of the ERK signaling pathway. Cell fractionation studies showed that only a small amount of p-ERK1/2 was translocated to the nucleus, with the majority retained in the cytoplasm. From coimmunoprecipitation studies, p-ERK was found to form stable heterotrimeric complexes with the D1 dopamine receptor and beta-arrestin2. In cells transfected with the dominant negative mutant of beta-arrestin2, the formation of such complexes was substantially inhibited. These data provide novel mechanistic insights into the role of ERK in the cytotoxicity mediated upon activation of the D1 dopamine receptor.
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PMID:D1 dopamine receptor mediates dopamine-induced cytotoxicity via the ERK signal cascade. 1524 97

Neuroblastomas are embryonal tumours of the sympatho-adrenal lineage with a clinical course ranging from spontaneous regression to fatal progression. The Phox2B homeobox transcription factor functions in the differentiation of the sympatho-adrenal lineage. Targets of Phox2B are, for example, genes of the (nor)adrenalin synthesis route, like Dopamine Beta Hydroxylase (DBH). Congenital Central Hypoventilation Syndrome was recently found to result from Phox2B mutations and two such patients in addition developed neuroblastoma. A germline mutation in Phox2B was identified in a family with hereditary neuroblastoma. Here, we report the first analysis of Phox2B in a series of 237 sporadic neuroblastomas and 22 cell lines. Six frameshift mutations were found in exons 2 and 3; including one in cell line SK-N-SH. Two patients showed de novo constitutional mutations. One of them was diagnosed with Haddad syndrome. All analysed cases expressed the mutated and wild-type Phox2B alleles. Ectopic expression of TrkA, the Nerve Growth Factor receptor, strongly downregulated Phox2B and DBH expression in cell line SH-SY5Y. However, TrkA and Phox2B showed a positive correlation in a panel of 66 neuroblastoma tumours. Although Phox2B mutations are infrequent (2.3%), they implicate a role for the Phox2B pathway in oncogenesis.
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PMID:The Phox2B homeobox gene is mutated in sporadic neuroblastomas. 1551 80

Expression of CCAAT/enhancer-binding protein beta (C/EBP beta) and growth-arrest DNA damage-inducible 153/C/EBP beta homology protein (GADD153/CHOP) increased after incubation of human neuroblastoma SH-SY5Y cells with a range of dopamine concentrations. Dopamine (100 microM) caused an increase in C/EBP beta expression between 2 and 12 h of treatment, with no evident intracellular morphological changes. Dopamine (500 microM) led to the appearance of autophagic-like vacuoles and a marked increase in GADD153/CHOP between 6 and 24 h of treatment. The expression of alpha-synuclein, the main protein of Lewy bodies in Parkinson's disease and other neurological disorders, increased with a profile similar to C/EBP beta. In addition, overexpression of C/EBP beta caused a concomitant increase in the expression of alpha-synuclein but not of GADD153. In contrast, the overexpression of GADD153 did not alter the expression of alpha-synuclein. Inhibition of JNK by SP600125 reduced increases in C/EBP beta and alpha-synuclein expression, whereas inhibition of both JNK and p38MAPK (with SB203580) blocked the increase in GADD153 expression. We conclude that dopamine, through a mechanism driven by stress-activated MAPKs, triggers C/EBP beta and GADD153 expression in a dose-dependent way. Given that the promoter region of the alpha-synuclein gene contains distinct zones that are susceptible to regulation by C/EBP beta, this factor could be involved in the increased expression of alpha-synuclein after dopamine-induced cell stress. GADD153 increase seems to be related with the endoplasmic reticulum stress, autophagy and cell death observed at high dopamine concentrations.
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PMID:Induction of C/EBP beta and GADD153 expression by dopamine in human neuroblastoma cells. Relationship with alpha-synuclein increase and cell damage. 1568 May 48

Recently, our laboratory demonstrated that human neuroblastoma cells (SH-SY5Y) are capable of synthesizing morphine, the major active metabolite of opium poppy. Now our experiments are further substantiated by extending the biochemical studies to the entire morphine pathway in this human cell line. L-[1,2,3-13C3]- and [ring-2',5',6'-2H3]dopa showed high isotopic enrichment and incorporation in both the isoquinoline and the benzyl moiety of the endogenous morphine. [2,2-2H2]Dopamine, however, was exclusively incorporated only into the isoquinoline moiety. Neither the trioxygenated (R,S)-[1,3-13C2]norcoclaurine, the precursor of morphine in the poppy plant, nor (R)-[1,3,4-2H3]norlaudanosoline showed incorporation into endogenous morphine. However, (S)-[1,3,4-2H3]norlaudanosoline furnished a good isotopic enrichment and the loss of a single deuterium atom at the C-9 position of the morphine molecule, indicating that the change of configuration from (S)- to (R)-reticuline occurs via the intermediacy of 1,2-dehydroreticuline. Additional feeding experiments with potential morphinan precursors demonstrated substantial incorporation of [7-2H]salutaridinol, but not 7-[7-2H]episalutaridinol, and [7-2H,N-C2H3]oripavine, and [6-2H]codeine into morphine. Human morphine biosynthesis involves at least 19 chemical steps. For the most part, it is a reflection of the biosynthesis in opium poppy; however, there is a fundamental difference in the formation of the key intermediate (S)-reticuline: it proceeds via the tetraoxygenated initial isoquinoline alkaloid (S)-norlaudanosoline, whereas the plant morphine biosynthesis proceeds via the trioxygenated (S)-norcoclaurine. Following the plant biosynthetic pathway, (S)-reticuline undergoes a change of configuration at C-1 during its transformation to salutaridinol and thebaine. From thebaine, there is a bifurcate pathway leading to morphine proceeding via codeine or oripavine, in both plants and mammals.
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PMID:How human neuroblastoma cells make morphine. 1593 6

We characterized dopamine toxicity in human neuroblastoma SH-SY5Y cells as a direct effect of dopamine on cell reductive power, measured as NADH and NADPH cell content. In cell incubations with 100 or 500 microM dopamine, the accumulation of dopamine inside the cell reached a maximum after 6 h. The decrease in cell viability was 40% and 75%, respectively, after 24 h, and was not altered by MAO inhibition with tranylcypromine. Dopamine was metabolized to DOPAC by mitochondrial MAO and, at 500 microM concentration, significantly reduced mitochondrial potential and oxygen consumption. This DA concentration caused only a slight increase in cell peroxidation in the absence of Fe(III), but a dramatic decrease in NADH and NADPH cell content and a concomitant decrease in total cell NAD(P)H/NAD(P)+ and GSH/GSSG and in mitochondrial NADH/NAD+ ratios. Dopaminechrome, a product of dopamine oxidation, was found to be a MAO-A inhibitor and a strong oxidizer of NADH and NADPH in a cell-free system. We conclude that dopamine may affect NADH and NADPH oxidation directly. When the intracellular concentrations of NAD(P)H and oxidized dopamine are similar, NAD(P)H triggers a redox cycle with dopamine that leads to its own consumption. The time-course of NADH and NADPH oxidation by dopamine was assessed in cell-free assays: NAD(P)H concentration decreased at the same time as dopamine oxidation advanced. The break in cell redox equilibrium, not excluding the involvement of free oxygen radicals, could be sufficient to explain the toxicity of dopamine in dopaminergic neurons.
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PMID:The decrease of NAD(P)H has a prominent role in dopamine toxicity. 1657 83

Dopaminergic human neuroblastoma SH-SY5Y cells were stably transformed to increase expression of alpha-synuclein, a Parkinson's disease-related protein. Transformed cells were more resistant to oxidative insults, showing a cytoprotective role of alpha-synuclein. The expression of redox chaperonins (DJ-1, HSP70, and 14-3-3) was evaluated by Western blotting. Expression of alpha-synuclein reduced HSP70 levels even in the presence of dopamine, with a twofold increase of DJ-1 in the absence of oxidants. DJ-1 is significantly reduced by dopamine, and even more by dopamine and Cu(II). Increased alpha-synuclein expression did not affect 14-3-3, although dopamine increased its level by 60% in wild-type cells. alpha-Synuclein not only upregulated DJ-1, but also shifted all DJ-1 forms to a single spot at pI=5.7 not observed in wild-type cells. Dopamine gradually restored the distribution of DJ-1 forms to a situation similar to wild-type cells, with the form at pI=6.1 progressively enriched under oxidative conditions.
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PMID:alpha-Synuclein protects SH-SY5Y cells from dopamine toxicity. 1697 83

Dopamine and norepinephrine are neurotransmitters which participate in various regulatory functions of the human brain. These functions are lost in neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. In this study, we used SK-N-MC neuroblastoma cells to investigate the cytotoxicities of high concentrations of dopamine and norepinephrine on neuronal cells. Dopamine, norepinephrine, as well as their corresponding synthetic agonists (SKF38393 and isoproterenol, respectively) triggered SK-N-MC cell death when applied at 50-100 muM persistently for 2 days. This catecholamine-induced cell death appears to be neuronal specific, as demonstrated by their inabilities of triggering apoptosis of A549 lung carcinoma cells and Cos-7 kidney fibroblasts. By pretreating SK-N-MC cells with target-specific inhibitors before administration of catecholamine, components of G protein signaling (i.e. G( s )/cAMP/PKA), monoamine oxidases, nitric oxide synthase, c-Jun N-terminal kinase and oxidative stress were found to be involved in this dopamine/norepinephrine-induced cytotoxicity, which subsequently led to caspase-dependent and -independent apoptotic responses as well as DNA degradation. In contrast, agonists of G( i )-coupled dopamine receptors and adrenergic receptors (quinpirole and UK14,304, respectively) were incapable of triggering apoptosis of SK-N-MC cells. Our results suggest that both G protein (G( s ))-mediated signaling cascade and oxidative stress participate in the dopamine/norepinephrine-induced neuronal apoptosis.
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PMID:Dopaminergic and adrenergic toxicities on SK-N-MC human neuroblastoma cells are mediated through G protein signaling and oxidative stress. 1713 23

Dopamine (DA) is an oxidant that may contribute to the degeneration of dopaminergic neurons. The present study demonstrates that DA-induced cytotoxicity in human-derived neurotypic cells, SH-SY5Y, is prevented by resveratrol, one of the major antioxidative constituents found in the skin of grapes. SH-SY5Y cells, a neuroblastoma cell line, treated with DA at 300 and 500 microM for 24 h underwent apoptotic death as determined by characteristic morphological features, including nuclear condensation, and loss of mitochondrial membrane potential (MMP). Flow cytometric analysis using Annexin V showed that DA can induce significant and severe apoptosis. Exposure to resveratrol (5 microM) for 1 h prior to the DA treatment attenuated DA-induced cytotoxicity, and rescued the loss of MMP. To investigate the apoptotic signaling pathways relevant to the restoration of DA-induced apoptosis by resveratrol, we carried out quantitative analysis of Bcl-2, caspase-3, and cleaved poly ADP-ribose polymerase (PARP) by immunoblot analysis. Resveratrol pretreatment led to a decrease in cleavage of PARP, an increase in the Bcl-2 protein, and activation of caspase-3. These results suggest that DA may be a potential oxidant of neuronal cells at biologically relevant concentrations. Resveratrol may protect SH-SY5Y cells against this cytotoxicity, reducing intracellular oxidative stress through canonical signal pathways of apoptosis and may be of biological importance in the prevention of a dopaminergic neurodegenerative disorder such as Parkinson disease.
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PMID:Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. 1760 92


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