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)

Human neuroblastoma cell lines comprise cellular counterparts of normal differentiation phenotypes arising from the developing neural crest Three distinct cell types have been isolated from cell lines: N-type cells with properties of embryonic sympathoadrenoblasts, S-type cells resembling nonneuronal Schwannian/glial/melanoblastic precursors, and I-type stem cells that can differentiate into either N- or S-type cells. Sympathoadrenoblasts from the normal neural crest further differentiate into neuronal or neuroendocrine cells. In this study, we show that malignant N-type neuroblasts likewise can differentiate futher along these same pathways. Retinoic acid and forskolin induce a neuronalphenotype, denoted morphologically by cell aggregation and increased neurite formation and biochemically by increases in neurofilament proteins, tyrosine hydroxylase, and secretogranin II and decrease inchromogranin A. By contrast, dexamethasone, a synthetic glucocorticoid, induces a chromaffin cell phenotype characterized by increased cell flattening, loss of neuritic processes, increased chromogranin A and tyrosine hydroxylase proteins, and decreased amounts of secretogranin II and neurofilaments. N-myc gene expression is upregulated by glucocorticoids; dexamethasone-treated N-type cells show significant (2.3- to 7.8-fold) increases in N-myc mRNA and protein steady-state levels. This effect is specific for glucocorticosteroids, is blocked by addition of the steroid receptor antagonist RU486, and involves direct activation of the N-myc promoter. These findings are the first to show that glucocorticoids upregulate N-myc expression in human neuroblastoma cells.
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PMID:Glucocorticoids induce neuroendocrine cell differentiation and increase expression of N-myc in N-type human neuroblastoma cells. 1239 56

9-cis Retinoic acid (RA) induces gene expression in neuroblastoma cells more effectively and with different kinetics than other RA isomers, and could be acting in part through Retinoid X Receptors (RXRs). The aim of this study was to characterise the effects of an RXR agonist and RXR homodimer antagonist on the induction of cellular RA binding protein II (CRABP-II) and RA receptor-beta (RARbeta) in neuroblastoma cells in response to different retinoids. The RXR agonist, LDG1069, was as effective as all-trans RA in inducing gene expression, but less effective than 9-cis RA. The RXR-homodimer antagonist, LG100754, inhibited the induction of CRABP-II mRNA in SH-SY5Y neuroblastoma cells by 9-cis RA or the RXR-specific agonist LGD1069, but had no effect when used with all-trans RA. Conversely, LG100754 did not inhibit induction of RARbeta mRNA by 9-cis or all-trans RA, or by LGD1069. RAR- and RXR-specific ligands used together induced CRABP-II and RARbeta as effectively as 9-cis RA. These results demonstrate the value of combining RXR- and RAR-specific ligands to regulate RA-inducible gene expression. The possibility that RXR-homodimers mediate, in part, the induction of CRABP-II by 9-cis RA and RXR-specific ligands is discussed.
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PMID:Retinoid signalling and gene expression in neuroblastoma cells: RXR agonist and antagonist effects on CRABP-II and RARbeta expression. 1239 10

Retinoic acid (RA) affects many cell types by either promoting their survival or inducing their differentiation. Dehydroepiandrosterone (DHEA), a precursor for both androgenic and estrogenic steroids and abundantly produced by brain, is known as an inhibitor of cell proliferation. Differentiation of a human neuroblastoma cell line (SK-N-BE) was evaluated measuring growth rate, motility, neurite extension and GAP-43 expression. We report that DHEA enhances the differentiating effect of RA on neuroblastoma cells via a signalling that is not RA receptor-mediated. Instead, we show a differential expression of matrix metalloproteinases: RA enhances the activity of MMP-2, whereas MMP-9 expression is up-regulated by DHEA. The concerted modulation of these proteinases may support the neurite outgrowth observed after co-treatment with the two drugs.
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PMID:Synergistic effect of retinoic acid and dehydroepiandrosterone on differentiation of human neuroblastoma cells. 1245 81

Retinoic acid-induced differentiation of SH-SY5Y human neuroblastoma cells results in the development of extensive neurite processes as well as changes in cell body morphology toward a neuronal phenotype. The authors have examined concurrent regulation of beta-amyloid precursor protein (APP) and inositol 1,4,5-trisphosphate receptor (insP(3)R) gene expression in SY5Y cells during neuronal differentiation. Of the multiple APP mRNA transcripts expressed in this cell line, retinoic acid treatment significantly increased the expression of APP(695) transcript while the level of total APP remained unchanged. In the same time course, neuronal differentiation decreased the expression of insP(3)R at both the mRNA and protein levels. These findings demonstrate an inverse relationship between APP and insP(3)R gene expression during neuronal differentiation of SH-SY5Y cells and suggest a possible change in intracellular calcium homeostasis.
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PMID:Regulation of beta-amyloid precursor protein and inositol 1,4,5-trisphosphate receptor gene expression during differentiation of a human neuronal cell line. 1269 70

Poor prognosis neuroblastoma (NB) tumors are marked by amplification and overexpression of N-myc. Retinoic acid (RA) decreases N-myc levels and induces cell cycle arrest in vitro and increases event-free survival in advanced stage NB patients. In this study, we investigated the mechanism(s) by which RA regulates cell cycle and how N-myc affects NB cell cycle progression. Constitutive N-myc overexpression stimulates increases in cyclin E-dependent kinase activity and decreases in p27 resulting in increased DNA synthesis. N-myc regulates p27 levels through an increase in targeting of p27 to the proteasome via cyclin E kinase-dependent phosphorylation of p27 and its ubiquitination. N-myc also stimulates an increase in proteasome activity. In RA-treated cells in which N-myc levels decline as p27 levels increase, degradation of p27 is also decreased. However, RA does not affect the activity of proteasome. The decrease in the degradation of p27 in RA-treated cells is due in part to a decrease in the N-myc stimulated phosphorylation of p27. However, RA also decreases Skp2 levels thus impairing the ability of p27 to be ubiquitinated. Thus, RA induces both N-myc-dependent and -independent mechanisms to minimize the degradation of p27 and arrest NB cell growth.
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PMID:Retinoic acid decreases targeting of p27 for degradation via an N-myc-dependent decrease in p27 phosphorylation and an N-myc-independent decrease in Skp2. 1270 Jun 51

Neuroblastoma, the most common extracranial solid tumour in children, may undergo spontaneous differentiation or regression, but the majority of metastatic neuroblastomas have poor prognosis despite intensive treatment. Retinoic acid and its analogues regulate growth and differentiation of neuroblastoma cells in vitro, and 13-cis retinoic acid has shown activity against human neuroblastomas in vivo. Fenretinide [N-(4-hydroxyphenyl)retinamide] has been identified as a synthetic retinoid able to induce apoptosis of numerous malignant cell lines in vitro, including neuroblastoma. Furthermore, in animal models, fenretinide has shown chemopreventive and therapeutic efficacy against several malignancies without any obvious signs of toxicity. To investigate the anti-neuroblastoma tumour growth effects of oral fenretinide in vivo we used a human neuroblastoma xenograft model. Nude rats with established neuroblastoma xenograft tumours were treated orally with fenretinide for 10 days. Five different doses of fenretinide were used ranging from 2.5 to 75 mg/rat/day (10-300 mg/kg). Tumour volumes and toxic side effects were monitored during treatment and tumour weights were recorded at autopsy. In this study we found no significant anti-tumour growth effects of fenretinide in vivo, when used as oral treatment of rats with established neuroblastoma xenograft tumours. Furthermore, there were no intra tumoural differences in treated compared to untreated tumours. However, because of the promising results of fenretinide on neuroblastoma growth in vitro, further in vivo studies are warranted using other modalities of drug administration.
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PMID:Evaluation of anti-tumour effects of oral fenretinide (4-HPR) in rats with human neuroblastoma xenografts. 1288 45

Retinoic acid (RA) is a potent regulator of morphogenesis, growth and cell differentiation. Incubation with RA causes arrest of proliferation and neurite extension in SH-SY5Y cells, a neuroblastoma cell line of human origin. In these cells, RA regulates the expression of the beta-amyloid precursor protein. The retinoid increases the levels of intracellular and secreted forms of APP (amyloid precursor protein), APP-mRNA levels and the activity of the APP promoter in transient transfection studies. These responses require long periods of exposition to the ligand, thus suggesting a nondirect effect of the RA receptors on the APP gene. Also in these cells, RA induces the expression of TrkB, the tyrosine kinase receptor for brain-derived neurotrophic factor (BDNF), and 4 days of pretreatment with retinoic acid confers BDNF responsiveness to the APP promoter.
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PMID:Induction of tyrosine kinase receptor b by retinoic acid allows brain-derived neurotrophic factor-induced amyloid precursor protein gene expression in human SH-SY5Y neuroblastoma cells. 1292 7

Tribromophenol is a pesticide with fungicide activity, presently used as a replacement of pentachlorophenol as a wood preservative, and as a flame retardant in electronic and electrotechnical devices. Retinoic acid differentiated and non-differentiated SH-SY5Y human neuroblastoma cell cultures were exposed to a range of concentrations of tribromophenol for 24, 48 and 72 h and the effects evaluated at morphological, basal cytotoxicity and biochemical levels. Neuroblastoma cell number, evaluated by quantification of total protein content, was increasingly inhibited in accordance with the concentration of tribromophenol and the exposure time period. According to the mean effective concentrations, differentiated cultures were nearly three times more sensitive than naive cells. Lysosomal function evaluated by the neutral red uptake was stimulated, particularly in non-differentiated cells. MTS metabolization was stimulated by all the treatments, with more potency at 24 h for differentiated cells. Acetylcholinesterase activity increased with the time of exposure in non-differentiated cells, while in differentiated cells the activity was doubled at 24 h. Morphological alterations were evident from 12.5 microM, showing hydropic degeneration and reduction in cell number, and from that concentration, piknosis and apoptotic bodies were observed. In conclusion, the main effects detected for tribromophenol were the induction of neuroblastoma cell differentiation, as expressed by the inhibition of cell growth and the increase in acetylcholinesterase activity with a critical cell concentration of 0.1 microM. Apoptosis was observed at high concentrations. The induction of cell differentiation and the special sensitivity of differentiated cells can explain some mechanisms involved in the embryotoxic and foetotoxic potential of tribromophenol.
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PMID:Tribromophenol induces the differentiation of SH-SY5Y human neuroblastoma cells in vitro. 1459 56

Unlike 13-cis-retinoic acid, the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide] induces apoptosis of neuroblastoma cells by mechanisms involving retinoic acid receptors and oxidative stress. After screening a cDNA array for apoptosis-related genes, the Bcl2-related protein Bak was identified as a fenretinide-inducible gene in SH-SY5Y neuroblastoma cells, and this was confirmed by Western blotting and flow cytometry. Although fenretinide acts synergistically in vitro with chemotherapeutic drugs, these drugs did not induce Bak expression. Retinoic acid receptor antagonists did not block the induction of Bak by fenretinide. Conversely, Bak induction was blocked by the antioxidant vitamin C. Overexpression of Bak increased apoptosis in both the presence and absence of fenretinide, whereas expression of antisense Bak inhibited fenretinide-induced apoptosis. Bak expression was also induced in cells overexpressing the stress-induced transcription factor GADD153, but Bak expression was inhibited in cells expressing an antisense GADD153 construct. These results suggest that Bak is a downstream mediator of an oxidative stress pathway leading to apoptosis of SH-SY5Y neuroblastoma cells in response to fenretinide.
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PMID:Bak: a downstream mediator of fenretinide-induced apoptosis of SH-SY5Y neuroblastoma cells. 1461 28

Retinoic acid (RA), an active metabolite of vitamin A, is a natural morphogen involved in development and differentiation of the nervous system. To elucidate signaling mechanisms involved in RA-induced neuritogenesis, we used human neuroblastoma SH-SY5Y cells, an established in vitro model for studying RA action, to examine the role of extracellular signal-regulated kinase (ERK) 1 and 2 in RA-induced neuritogenesis and cell survival. From immunoblotting experiments, we observed that RA induced delayed but persistent ERK1 and ERK2 phosphorylation (until 96 hr) that was reduced significantly by the specific mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor U0126. For the subsequent studies we chose 24 hr as the reference time. Inhibition of ERK activation did not affect RA-induced neuritogenesis (percentage of neurite-bearing cells and neurite length) but significantly reduced cell survival. In addition, we analyzed the signaling pathway that mediates ERK activation. Our results suggest that RA-induced ERK phosphorylation does not follow the classic Raf kinase-dependent pathway. Protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI 3-K) are possible alternative kinases involved in the ERK signaling pathway. In fact, in the presence of the specific PKC inhibitor GF 109203X, or the specific PI 3-K inhibitor wortmannin, we observed a significant dose-dependent reduction in ERK phosphorylation. RA-induced neuritogenesis and cell survival were reduced by GF 109203X in a concentration-dependent manner. These results suggest that rather than ERK1 and ERK2, it is PKC that plays an important role during early phases of RA-induced neuritogenesis.
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PMID:Retinoic acid-induced neuritogenesis of human neuroblastoma SH-SY5Y cells is ERK independent and PKC dependent. 1470 45


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