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)

Aspartyl (asparaginyl) beta-hydroxylase (AAH) is overexpressed in various malignant neoplasms, and high levels of immunoreactivity mainly occur in infiltrating or metastasized tumors. In addition, AAH is abundantly expressed in normally invasive placental trophoblastic cells. These observations led to the hypothesis that AAH may have a role in motility and aggressive behavior of tumor cells. The present study demonstrates that AAH is overexpressed in primary human malignant neuroectodermal tumors, including medulloblastomas and neuroblastomas, and that AAH expression is at a low level or undetectable in the normal mature brain. In the Sy5y neuroblastoma cell line, endogenous expression of the approximately 86-kd AAH protein was demonstrated by Western blot analysis, and immunoreactivity predominantly localized to the cell surface by immunocytochemical staining and FACS analysis. Sy5y cells that were stably transfected with the human AAH cDNA had increased levels of proliferating cell nuclear antigen and Bcl-2, and reduced levels of p21/Waf1 and p16. In addition, increased AAH expression enhanced Sy5y cell motility, whereas antisense oligodeoxynucleotide inhibition of AAH significantly reduced Sy5y cell motility and increased the levels of p21/Waf1 and p16. The findings suggest that AAH overexpression contributes to the malignant phenotype of neuroectodermal tumor cells by increasing motility and enhancing proliferation, survival, and cell cycle progression. Because AAH expression is at a low level or undetectable in normal brain, the AAH gene may be a target for treating primitive neuroectodermal tumors.
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PMID:Role of the aspartyl-asparaginyl-beta-hydroxylase gene in neuroblastoma cell motility. 1211 90

PCTAIRE-1 is a CDK-related protein kinase found in terminally differentiated cells in brain and testis, and in many immortalised and transformed cell lines. Bacterially expressed PCTAIRE is completely inactive as a protein kinase, but is a very good substrate for protein kinase A (PKA), which phosphorylates a total of four sites in the N-terminus of PCTAIRE-1. Phosphorylation of one of these sites, Ser119, generates a 14-3-3 binding site, which is functional in vitro as well as in vivo. Mutation of another PKA site, Ser153, to an alanine residue generated an activated kinase in transfected mammalian cells. This activity was comparable to that of CDK5 activated by a bacterially expressed, truncated version of p35(nck), p21. Gel filtration analysis of a brain extract suggested that monomeric PCTAIRE-1 was the active species, implying that PCTAIRE-1 may not be a true CDK, in that it does not require a partner (cyclin-like) subunit for kinase activity. Finally, we found that various forms of PCTAIRE-1 transfected into neuroblastoma cell lines could either promote or inhibit neurite outgrowth, suggesting a potential role for the PCTAIRE-1 gene product in the control of neurite outgrowth.
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PMID:Regulation of the CDK-related protein kinase PCTAIRE-1 and its possible role in neurite outgrowth in Neuro-2A cells. 1215 78

Tetrandrine (TET), a plant alkaloid, is known primarily as a non-selective Ca(2+) channel blocker. On the contrary to the cytoprotective effect on ischemia/reperfusion injury, TET has also been reported to cause cytotoxicity. In this study, we wished to understand the apparently disparate effects of this potential drug and thus investigated molecular mechanisms on proliferation and apoptosis and its effect on oxidative stress-induced apoptosis in Neuro 2a mouse neuroblastoma cells. We showed that TET, at high concentrations, induced cell cycle arrest and apoptosis through oxidative stress with following observations. Firstly, 10 microM TET elevated the reactive oxygen species (ROS) level and accordingly depleted glutathione (GSH) content. Secondly, pretreatment with antioxidants (NAC or GSH) protected cells from TET-induced apoptosis. We also demonstrated that treatment with 10 microM TET caused not only induction of p53, p21(waf1), and Bax, but also nuclear translocation of p53 and hypo-phosphorylation of pRb concurrently. Our important finding is that the concentration-dependent dual effect of TET, either inhibiting or promoting cell death induced by H(2)O(2) was observed, probably through regulating redox balance, which was well reflected on the GSH content in each condition. Besides, inhibition of Ca(2+) influx protected cells from H(2)O(2)-induced apoptosis even in the presence of 10 microM TET. Taken together, our data suggest that TET regulation of cellular redox states may play a major role in its dual action of cytotoxicity and cytoprotection.
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PMID:Tetrandrine cytotoxicity and its dual effect on oxidative stress-induced apoptosis through modulating cellular redox states in Neuro 2a mouse neuroblastoma cells. 1217 98

Previous reports raised question as to whether 8-chloro-cyclic adenosine 3,5-monophosphate (8-Cl-cAMP) is a prodrug for its metabolite, 8-Cl-adenosine which exerts growth inhibition in a broad spectrum of cancer cells. The present study was carried out to clarify overall cellular affects of 8-Cl-cAMP and 8-Cl-adenosine on SK-N-DZ human neuroblastoma cells by systematically characterizing gene expression using radioactive human cDNA microarray. Microarray was prepared with PCR-amplified cDNA of 2,304 known genes spotted on nylon membranes, employing (33)P-labeled cDNAs of SK-N-DZ cells as a probe. The expression levels of approximately 100 cDNAs, representing about 8% of the total DNA elements on the array, were altered in 8-Cl-adenosine- or 8-Cl-cAMP-treated cells, respectively. The genome-wide expression of the two samples exhibited partial overlaps; different sets of up-regulated genes but the same set of down-regulated genes. 8-Cl-adenosine treatment up-regulated genes involved in differentiation and development (LIM protein, connexin 26, neogenin, neurofilament triplet L protein and p21(WAF1/CIP1)) and immune response such as natural killer cells protein 4, and down-regulated ones involved in proliferation and transformation (transforming growth factor-beta, DYRK2, urokinase-type plasminogen activator and proteins involved in transcription and translation) which were in close parallel with those by 8-Cl-cAMP. Our results indicated that the two drugs shared common genomic pathways for the down-regulation of certain genes, but used distinct pathways for the up-regulation of different gene clusters. Based on the findings, we suggest that the anti-cancer activity of 8-Cl-cAMP results at least in part through 8-Cl-adenosine. Thus, the systematic use of DNA arrays can provide insight into the dynamic cellular pathways involved in anticancer activities of chemotherapeutics.
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PMID:Genome-wide expression profiling of 8-chloroadenosine- and 8-chloro-cAMP-treated human neuroblastoma cells using radioactive human cDNA microarray. 1221 10

Iron (Fe) is an obligate requirement for life and it is well known that Fe depletion leads to G(1)/S arrest and apoptosis. These facts, together with studies showing that Fe chelators can inhibit the growth of aggressive tumours such as neuroblastoma, suggest that Fe-deprivation may be an important therapeutic strategy. To optimise the anti-proliferative effects of Fe chelators, the role of Fe in cell cycle control requires intense investigation. For many years, Fe chelators were known to prevent the activity of the R2 subunit of ribonucleotide reductase (RR) that catalyzes the conversion of ribonucleotides into deoxyribonucleotides (dNTPs) for DNA synthesis. In addition, Fe depletion may also inhibit the newly identified p53-inducible form of this molecule called p53R2. This protein has the same Fe-binding sites as found in R2, and its activity is thought to supply dNTPs for the critical process of DNA repair. Iron chelation also causes hypophosphorylation of the retinoblastoma protein (pRb) and decreases the expression of cyclins A, B and D, which are vital for cell cycle progression. Other regulatory molecules whose expression is affected by Fe depletion include p53 and hypoxia inducible factor-1alpha (HIF-1alpha). The levels of p53 increase following Fe chelation via the ability of HIF-1alpha to bind and stabilize p53. The activity of HIF-1alpha is controlled by an Fe-dependent enzyme known as HIF-alpha prolyl hydroxylase (PH). Chelation of Fe from this enzyme inhibits its activity, leading to stabilization of HIF-1alpha and the subsequent effects on downstream targets critical for angiogenesis and tumour growth. The levels of p53 may also increase after Fe chelation by phosphorylation of this protein at serine-15 and -37. This prevents the interaction of p53 with murine double minute-2 (mdm-2) and its degradation. Iron chelation also markedly increases the mRNA levels of the p53-inducible cyclin-dependent kinase (cdk) inhibitor, p21(WAF1/CIP1). Surprisingly, the increase in p21(WAF1/CIP1) mRNA was not reciprocated at the protein level, and this may result in cell cycle dysregulation. This review will focus on the molecular mechanisms induced following Fe chelation and the role of Fe in cell cycle progression.
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PMID:The role of iron in cell cycle progression and the proliferation of neoplastic cells. 1224 9

Levels of the transcription factor B-myb must be down-regulated to allow terminal differentiation of neuroectodermal cells and yet its constitutive expression induces early markers of neural differentiation. Thus, we investigated potential mechanisms of enhanced B-myb activity in early stages of neural differentiation. We report here that B-myb expression does not decrease, cyclin A and Sp1 levels remain constant while p21 levels increase continuously upon retinoic acid-induced differentiation of the LAN-5 neuroblastoma cell line. In contrast, cyclin D1 expression is down-regulated at the onset of the differentiative process by protein destabilization. Luciferase assays of promoter activity indicate that B-myb-dependent transactivation is enhanced in LAN-5 cells treated with retinoic acid (RA) for 24 h. The enhancement is independent from cyclin A but is suppressed by a degradation-resistant mutant form of cyclin D1. The importance of cyclin D1 in controlling B-myb activity is further suggested by co-immunoprecipitation experiments, showing that the amount of cyclin D1 co-immunoprecipitated with B-myb decreased after RA treatment. Thus, B-myb may play an active role in the early stages of differentiation when its transactivation activity is enhanced as a consequence of cyclin D1 down-modulation.
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PMID:Cyclin D1-dependent regulation of B-myb activity in early stages of neuroblastoma differentiation. 1240 22

The signaling pathway for DNA damaging drug-triggered apoptosis was examined in a chemosensitive human neuroblastoma cell line, SH-SY5Y. Doxorubicin and etoposide induce rapid and extensive apoptosis in SH-SY5Y cells. After the drug treatment, p53 protein levels increase in the nucleus, leading to the induction of its transcription targets p21(Waf1/Cip1) and MDM2. Inactivation of p53, either by the human papillomavirus type 16 E6 protein or by a dominant-negative mutant p53 (R175H), completely protects SH-SY5Y cells from drug-triggered apoptosis. Cytochrome c and caspase-9 function downstream of p53 in mediating the drug-triggered apoptosis in SH-SY5Y cells. In drug-treated cells, cytochrome c is released, and caspase-9 becomes activated. Inactivation of p53 blocks cytochrome c release and caspase-9 activation. Furthermore, drug-induced cell death can be prevented by expression of a dominant-negative mutant of caspase-9. These findings define a molecular pathway for mediating DNA damaging drug-induced apoptosis in the human neuroblastoma SH-SY5Y cells and suggest that inactivation of essential components of this apoptotic pathway may confer drug resistance on neuroblastoma cells.
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PMID:p53 mediates DNA damaging drug-induced apoptosis through a caspase-9-dependent pathway in SH-SY5Y neuroblastoma cells. 1247 64

We determined the in vitro biological activities of 1 alpha, 25-dihdroxyvitamin D(3) (1,25-D(3)) and its analogue, 20-epi-22-oxa-24a, 26a, 27a-trihomo-1 alpha, 25 (OH)(2) vitamin D(3) (KH1060) in six human neuroblastoma (NB) cell lines (SH-SY5Y, NB69, SK-N-AS, IMR5, CHP-134, NGP). The ability of these compounds to inhibit cell growth and DNA synthesis was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and BrdU incorporation, respectively. The induction of cell death was monitored by caspase-3 activity. Their antineoplastic effect was assessed by clonal proliferation in soft agar. KH1060 was more effective than 1,25 D(3) in inhibiting cell growth and DNA synthesis. The IC-(50) (inhibition of 50% cell viability) indicated that KH1060 was about 10-20-fold more potent than 1,25 D(3). This growth inhibition was also accompanied by induction of caspase-3 activity, indicating that these compounds induce cell death in a caspase-dependent fashion. Moreover, KH1060 exerted potent antineoplastic activity by suppressing the clonal proliferation of the six NB cells. For the first time we demonstrate that KH1060 induces the expression of retinoic acid receptor-beta and p21(Cip1) suggesting that these proteins in part mediate the growth inhibitory effects. Taken together, all the six NB cells were more susceptible to growth inhibition by KH1060 than 1,25-D(3), suggesting its possible use in NB to potentiate the action of retinoids, which are in clinical use for this disease.
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PMID:Anti-proliferative effects of 20-epi-vitamin-D3 analogue, KH1060 in human neuroblastoma: induction of RAR-beta and p21(Cip1). 1253 77

Many studies have revealed the free radical nitric oxide (NO) to be an important modulator of vascular and neuronal physiology. It also plays a developmental role in regulating synapse formation and patterning. Recent studies suggest that NO may also mediate the switch from proliferation to differentiation during neurogenesis. Many mechanisms of this response are conserved between neuronal precursor cells and the cells of the vascular system, where NO can inhibit the proliferative response of endothelial and smooth-muscle cells to injury. In cultured neuroblastoma cells, NO synthase (NOS) expression is increased in the presence of various growth factors and mitogens. Subsequent production of NO leads to cessation of cell division and the acquisition of a differentiated phenotype. The inhibitory action of NO on neuroblast proliferation has also been demonstrated in vivo for vertebrate and invertebrate nervous systems, as well as in the adult brain. Potential downstream effectors of NO include the second messenger cyclic GMP, activation of the tumor-suppressor genes p53 and Rb, and the cyclin-dependent kinase inhibitor p21. These studies highlight a new role for NO in the nervous system, as a coordinator of proliferation and patterning during neural development and adult neurogenesis.
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PMID:Regulation of neuronal proliferation and differentiation by nitric oxide. 1277 82

The antiproliferative effects of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and its epimer, 20-epi-1alpha,25-dihydroxyvitamin D(3) [20-epi-1,25(OH)(2)D(3)], in six human neuroblastoma (NB) cell lines (SH-SY5Y, NB69, SK-N-AS, IMR5, CHP134, and NGP) were investigated. We determined the ability of 1,25(OH)(2)D(3) and 20-epi-1,25(OH)(2)D(3) to influence cell viability by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell proliferation by bromodeoxyuridine (BrdU) incorporation, and their antineoplastic effect on colony formation in a soft agar assay. A concentration-dependent decrease in cell viability, inhibition of DNA synthesis, and suppression of clonal proliferation was observed with both compounds. 20-epi-1,25(OH)(2)D(3) was more potent in suppressing the proliferation of all six NB cell lines. To understand the mechanisms of action, we examined the effect of 20-epi-1,25(OH)(2)D(3) on the Myc-Id2 cell proliferative network and also on key regulators of the cell cycle. For the first time, we show that 20-epi-1,25(OH)(2)D(3) down-regulated Myc and Id2 expression by western blot analysis. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that 20-epi-1,25(OH)(2)D(3) induced the expression of retinoic acid receptor-beta and p21(Cip1), and down-regulated the expression of cyclin D1 resulting in decreased phosphorylation of retinoblastoma protein (pRB). In sum, we show that 20-epi-1,25(OH)(2)D(3) exerts strong antiproliferative effects by regulating key growth control networks (Myc-Id2-pRB) in NB cells.
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PMID:Effect of 20-epi-1alpha,25-dihydroxyvitamin D3 on the proliferation of human neuroblastoma: role of cell cycle regulators and the Myc-Id2 pathway. 1278 74


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