UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sequential steps in the activation of the pro-apoptotic protein Bax are described for cells with different sensitivity to cytotoxins. SH-EP1 and SH-SY5Y human neuroblastoma cells, derived from a single precursor cell line, differed in their sensitivity to taxol but showed the same sensitivity to cisplatin. Both drugs, in both cell lines, induced exposure of a constitutively occluded N-terminal epitope of Bax. This was reversible and occurred before the translocation of cytosolic Bax to mitochondria. The N-terminal change in Bax, its subsequent movement to mitochondria and its dimerization/complex formation were insufficient for commitment to death, occurring in the same proportion of cells that either maintained (SH-SY5Y) or lost (SH-EP1) clonogenic survival after taxol treatment. Suppression of taxol-induced apoptosis occurred upstream of cytochrome c release from mitochondria in SH-SY5Y cells. The data suggest that a further drug damage-induced event occurs after Bax dimerization/complex formation but prior to cytochrome c release. This event was absent in the taxol-resistant cells.
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PMID:Damage-induced Bax N-terminal change, translocation to mitochondria and formation of Bax dimers/complexes occur regardless of cell fate. 1170 2

The human p73 gene is a homolog of p53, which has been localized to chromosome 1p36 in a region that is frequently deleted in neuroblastoma. Transfection of the p73 gene into neuroblastoma cells that lack detectable p73 protein has been shown to result in growth suppression and to induce neuronal differentiation. In this study, we have identified by means of restriction landmark genome scanning (RLGS) a genomic fragment that was frequently reduced in intensity in neuroblastomas. The cloned fragment contained exon 1 of p73 as well as intronic and promoter sequences. We investigated the genomic and expression status of p73 and N-myc in 34 neuroblastoma tumors and 12 neuroblastoma cell lines. Approximately a third of neuroblastomas in our series exhibited deletion of p73. Most tumors analyzed exhibited reduced expression of p73, as determined by quantitative RT-PCR, in the absence of detectable p73 gene deletion. The reduced expression of p73 correlated with overexpression of N-myc in a statistically significant manner. The N-myc gene was transfected into two neuroblastoma cell lines that lacked N-myc amplification to determine its effect on p73 RNA levels. p73 was detectable at low level by RT-PCR in untransfected SK-N-AS cells and became undetectable following N-myc transfection, whereas in SH-EP1 cells, p73 levels were substantially reduced following transfection but remained detectable. Our data suggest that the N-myc gene modulates expression of p73, allowing neuroblastoma cells to escape the growth suppressing properties of p73.
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PMID:N-myc modulates expression of p73 in neuroblastoma. 1219 2

The NFkappaB transcription factors can both promote cell survival and induce apoptosis depending on cell type and context. Neuroblastoma (NB) cells display two predominant culture phenotypes identified as N- and S-types. Malignant S-type cells express neither high levels of MYCN nor Bcl-2, suggesting that other survival mechanisms are important. We characterized NFkappaB activity in S-type cells and determined its role in their survival. S-type lines (SH-EP1 and SK-N-AS) were treated with pyrrolidine dithiocarbamate (PDTC), a NFkappaB inhibitor, or l-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK), a serine protease inhibitor that blocks IkappaBalpha degradation. Both agents induced cell death, suggesting that constitutive NFkappaB activity is required for survival. The transient expression of a super-repressor IkappaBalpha mutant killed S-type cells. The inhibition of NFkappaB produced an apoptotic response characterized by the collapse of the mitochondrial transmembrane electrochemical gradient, caspase-9 activation, and apoptotic DNA changes. Constitutive NFkappaB DNA binding activity specifically involving p65 and p50 was demonstrated in S- but not N-type cells by electromobility supershift and gene reporter assays. This study demonstrates a role for NFkappaB in the survival of S-type NB tumor cells and suggests that NFkappaB activity and function differ according to NB tumor cell phenotype.
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PMID:Constitutively active NFkappa B is required for the survival of S-type neuroblastoma. 1219 14

Stromal or S-type tumor cells are a distinct lineage found in neuroblastoma tumors and have an important role in the biology of this disease. Anticancer agents induce apoptosis through death receptor- and mitochondria-initiated pathways. The object of this work was to determine the involvement of these pathways in the response to doxorubicin (Dox) and cisplatin (CDDP) in S-type neuroblastoma cells. Both drugs activated caspase-9 and caspase-3 but not caspase-8. Caspase-9-specific inhibition blocked S-type cell death induced by Dox. SH-EP1 cells transfected to express dominant negative mutant caspase-9, but not those expressing DN caspase-8, were resistant to Dox- and CDDP-induced apoptosis. The lack of caspase-8 involvement in chemotherapy-induced death was not the result of an intrinsic inability of these cells to activate this enzyme because when they were treated with tumor necrosis factor-related apoptosis-inducing ligand, caspase-8 was activated. We also found that both drugs up-regulated CD95/Fas expression but that CD95/Fas signaling was not necessary for cell killing. Experiments testing the response of chemotherapy-treated cells to agonists of the CD95/Fas receptor established that Dox and CDDP treatment sensitizes cells to CD95/Fas killing. Together, these results are consistent with a model in which caspase-9 is of central importance in the death mechanism utilized by these drugs in S-type cells. Although the death response is not dependent on CD95/Fas, concomitant stimulation of this receptor amplifies the death response in drug-treated cells.
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PMID:Chemotherapy-induced apoptosis of S-type neuroblastoma cells requires caspase-9 and is augmented by CD95/Fas stimulation. 1461 34

Hypoxia is widespread in solid tumors as a consequence of poorly structured tumor-derived neovasculature. Direct measurement of low oxygen levels in a range of adult tumor types has correlated tumor hypoxia with advanced stage, poor response to chemotherapy and radiotherapy, and poor prognosis. Little is known about the importance of hypoxia in pediatric tumors; therefore, we evaluated the effects of hypoxia on the response of the neuroblastoma cell lines SH-EP1 and SH-SY5Y to the clinically relevant drugs, vincristine, etoposide, and cisplatin. Short periods of hypoxia (1% O2) of up to 16 hours had no effect on drug-induced apoptosis or clonogenic survival. Prolonged hypoxia of 1 to 7 days leads to reduction in vincristine- and etoposide-induced apoptosis in SH-SY5Y and SH-EP1 cells, and this was reflected in increased clonogenic survival under these conditions. Neither short-term nor prolonged hypoxia had any effect on the clonogenic response to cisplatin in SH-SY5Y cells. Hypoxia-inducible factor-1 (HIF-1) alpha was stabilized in these cell lines within 2 hours of hypoxia but was no longer detectable beyond 48 hours of hypoxia. Up-regulation of carbonic anhydrase IX showed HIF-1alpha to be transcriptionally active. Down-regulation of HIF-1alpha by short hairpin RNA interference and the small-molecule 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole reduced hypoxia-induced drug resistance. These results suggest that prolonged hypoxia leads to resistance to clinically relevant drugs in neuroblastoma and that therapies aimed at inhibiting HIF-1alpha function may be useful in overcoming drug resistance in this tumor.
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PMID:Chronic hypoxia promotes hypoxia-inducible factor-1alpha-dependent resistance to etoposide and vincristine in neuroblastoma cells. 1698 58

Neuroblastoma is the most common extracranial solid malignancy in children. The disease possesses a broad range of clinical phenotypes with widely varying prognoses. Numerous studies have sought to identify the associated genetic abnormalities in the tumour, resulting in the identification of useful prognostic markers. In particular, the presence of multiple copies of the MYCN oncogene (referred to as MYCN amplification) has been found to confer a poor prognosis. However, the molecular pathways involved are as yet poorly defined. Metabolite profiles generated by in vitro (1)H MRS provide a means of investigating the downstream metabolic consequences of genetic alterations and can identify potential targets for new agents. Thirteen neuroblastoma cell lines possessing multiple genetic alterations were investigated; seven were MYCN amplified and six MYCN non-amplified. In vitro magic angle spinning (1)H MRS was performed on cell suspensions, and the spectra analysed to obtain metabolite concentration ratios relative to total choline (tCho). A principal component analysis using these concentration ratios showed that MYCN-amplified and non-amplified cell lines form separate classes according to their metabolite profiles. Phosphocholine/tCho and taurine/tCho were found to be significantly raised (p < 0.05) and glycerophosphocholine/tCho significantly reduced (p < 0.05) in the MYCN-amplified compared with the MYCN non-amplified cell lines (two-tailed t test). (1)H MRS of the SH-EP1 cell line and an isogenic cell line transfected with the MYCN oncogene also showed that MYCN oncogene over-expression causes alterations in phosphocholine, glycerophosphocholine and taurine concentrations. Molecular pathways of choline and taurine metabolism are potential targets for new agents tailored to MYCN-amplified neuroblastoma.
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PMID:1H MRS identifies specific metabolite profiles associated with MYCN-amplified and non-amplified tumour subtypes of neuroblastoma cell lines. 1750 15

The aim of this study was to explore the effect of 0NO-54918-07, a stable prostacyclin analogue, on the current-voltage (IV) curve and the intracellular Ca2+ concentration [Ca2+]i of NG108-15 neuroblastoma x glioma hybrid cells. The IV curve was measured with ramp pulses from -70 to 0 mV, and [Ca2+]i was determined with Fura 2. Bath application of 0.2 muM ONO-54918-07 reversibly increased the holding current at -70 mV by -81.1 +/- 14.8 pA (mean +/- SEM, n = 35) and the slope of the IV curve between -70 and -50 mV by the factor 2.24 +/- 0.24. The effect of 0.2 microM prostaglandin PGE1 was similar (DeltaI (hold) = -96.1 +/- 29.9 pA, g/g (control) = 2.72 +/- 0.44, n = 9). ONO-54918-07 concentrations of 0.04, 2 and 6 microM were also effective. From the dose-response curve, the concentration for the half maximal effect was obtained as 0.054 microM. When cells did not respond to ONO-54918-07, an effect could sometimes be elicited by a ramp pulse or by a second ONO-54918-07 application 30-50 min after the first. The effect of ONO-54918-07 was not affected by pre-treatment with the EP1 antagonists ONO-8713 or SC-51089. However, a 14-40 min pre-treatment with 1 microM RO3244794, a selective prostacyclin receptor (IP) antagonist, abolished the effect of 0.2 microM PGE1. The effect of 0.2 microM ONO-54918-07 vanished completely in the presence of 5 microM RO32446794. ONO-54918-07 and PGE1 produced a slow increase in [Ca2+]i that lasted at least 6 min. Delta[Ca2+]i induced by both substances reached approximately 12% of the peak Delta[Ca2+]i induced by application of bradykinin. In only a few cells, PGE1 produced a brief, transient rise of [Ca2+]i. Using reverse transcriptase polymerase chain reaction, a prominent expression of the IP was detected in NG108-15 cells. It is concluded that ONO-54918-07 mimics the effect of PGE1, supporting the notion that the PGE1 effect on NG108-15 cells is mediated by IP receptors.
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PMID:ONO-54918-07, a stable prostacyclin analogue, mimics the effect of prostaglandin PGE1 on NG108-15 cells. 1795 10

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in substantia nigra with unknown etiology. Neuropathology seen in the brains of PD patients can be closely mimicked by MPP(+)-induced neurotoxicity in vitro. In this study, we used an S-type human neuroblastoma cell line (SH-EP1) as a model to investigate the involvement of NF-kappaB and JNK pathways in MPP(+)-induced neurotoxicity. We show that NF-kappaB was activated by MPP(+) as evidenced by NF-kappaB p65 nuclear translocation, the increased DNA binding activity and a rapid phosphorylation of NF-kappaB inhibitor (IkappaBalpha). NF-kappaB partially mediated the neurotoxicity of MPP(+), as suggested by the reduction of MPP(+)-induced cell death by both a specific IkappaB kinase (IKK) inhibitor and a dominant negative form of IkappaBalpha (IkappaBalpha-M). Besides NF-kappaB, JNK and c-Jun/AP-1 were also activated upon MPP(+) stimulation. Inhibition of JNK activation with a specific JNK inhibitor partially reduced the MPP(+)-mediated cell death. Similarly, inhibition of c-Jun/AP-1 activation, either by a dominant negative c-Jun or c-Jun/AP-1 inhibitor, significantly attenuated MPP(+)-mediated cell death. These results suggest that both JNK and c-Jun/AP-1 activation are pro-apoptotic. Furthermore, we provide clear evidence for the existence of a crosstalk between the NF-kappaB and JNK signaling as MPP(+)-induced activation of JNK and c-Jun/AP-1 was strongly down-regulated in IkappaBalpha-M cells. In conclusion, we demonstrate that in SH-EP1 cells MPP(+)-induced neurotoxicity is partially mediated by NF-kappaB which in turn acts on the activation of JNK and c-Jun/AP-1. These results may point to a combined inhibition of NF-kappaB and JNK as a new approach to PD therapy.
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PMID:NF-kappaB mediates MPP+-induced apoptotic cell death in neuroblastoma cells SH-EP1 through JNK and c-Jun/AP-1. 1977 65

Prostaglandin E(2) (PGE(2)) is a key lipid-derived compound which mediates important physiological functions in the nervous system via activation of four EP receptors (EP1-4). Recent studies have shown that altered PGE(2) signalling due to abnormal lipid peroxidation and oxidative stress may underlie some pathologies of the nervous system. The prenatal exposure to the drug misoprostol, a prostaglandin type E analogue, has also been linked to a number of neurodevelopmental defects. In the present study, we use ratiometric calcium imaging with fura-2AM as a calcium indicator to determine the effects of PGE(2) and misoprostol on calcium homeostasis in growth cones of mouse neuroblastoma (Neuro-2a) cells. Our results show that both drugs increase the amplitude of calcium transients in growth cones of Neuro-2a cells and induce neurite retraction. Moreover, quantitative real-time PCR also revealed that the mRNA expression level of the four EP receptors was significantly higher during the neurogenesis period in mouse indicating the importance of PGE(2) signalling in the nervous system.
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PMID:Prostaglandin E(2) and misoprostol induce neurite retraction in Neuro-2a cells. 2059 4

Misoprostol, a prostaglandin type E analogue, has been implicated in a number of neurodevelopmental disorders. However, its mode of action in the nervous system is not well understood. Misoprostol acts on the same receptors as prostaglandin E(2) (PGE(2)), a natural lipid-derived compound, which mediates important physiological functions in the nervous system via activation of four EP receptors (EP1-4). In this study we use a ratiometric calcium imaging with fura-2 AM as a calcium indicator to show that misoprostol alters intracellular calcium levels in mouse neuroblastoma (Neuro-2a) cells via similar mechanisms as PGE(2). We demonstrate that the misoprostol-induced increase in calcium is mediated by a protein kinase A (PKA)-dependent mechanism and that the EP4 receptor signaling pathway may play an inhibitory role on calcium regulation. Overall, this study provides further support for the involvement of PGE(2) signaling in calcium homeostasis and suggests its important role in the nervous system.
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PMID:Misoprostol elevates intracellular calcium in Neuro-2a cells via protein kinase A. 2067 71

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