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)

Proteasome activity is essential during cAMP-induced terminal differentiation of a murine neuroblastoma cell line (NBP2). However, the mechanisms through which proteasome affects NBP2 differentiation have not been characterized. We hypothesized that proteasome is required to implement the differentiation-mediated effects on cell cycle, and its partial inhibition during differentiation may have adverse consequences. Here we show that partial inhibition of proteasome during cAMP-induced differentiation of NBP2 cells causes apoptosis. Whereas differentiation induced growth arrest at G1 phase, partial proteasome inhibition during differentiation resulted in the accumulation of cells at G2M phase. Cell cycle data correlated with the level of cyclin-dependent kinase inhibitors p21WAF and p27Kip1, and cyclin A. While the level of p21 and p27 increased, the level of cyclin A decreased upon differentiation. In contrast, cells treated with proteasome inhibitor in the presence of cAMP-inducing agents showed increased levels of p21 and cyclin A early in the course of differentiation. However, the level of p21 and p27, but not cyclin A, decreased later during concomitant differentiation and partial proteasome inhibition when cells were undergoing apoptosis. Our data suggest that differentiation-mediated growth arrest is dependent on the temporal activity of cell cycle proteins. Partial inhibition of proteasome interferes with differentiation events partly by stabilizing cell cycle proteins and this triggers apoptosis. Thus, differentiating drugs combined with partial proteasome inhibition may impart higher therapeutic efficacy than differentiating agents alone for the treatment of neuroblastoma tumors.
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PMID:Concomitant differentiation and partial proteasome inhibition trigger apoptosis in neuroblastoma cells. 1281 50

In normal cells in which DNA has been damaged, p53 induces the expression of p21(Waf1/Cip1); p21, in turn, binds to cyclin-dependent kinase 2 (cdk2) and inhibits its function. Inhibition of cdk2 results in cell cycle arrest in G(0)-G(1). Although p53 is transcriptionally active and induces p21 expression in neuroblastoma (NB) cells, the G(0)-G(1) checkpoint is attenuated. Here we report that the mechanism that mediates this defect in NB cells is the inability of p21 to bind to, or inhibit the activity of cdk2. However, when recombinant p21 protein was added to NB cell extracts in vitro, the protein inhibited the activity of cdk2. This finding suggests that endogenous p21 protein in NB cells is inactive and may be bound either to a protein complex or in a conformation that precludes its binding to cdk2. The dysfunction of p21 in NB cells represents a novel mechanism by which the G(0)-G(1) cell cycle checkpoint can be inactivated. This mechanism may be important in regulating the growth of NB and potentially other types of tumors. Cdk inhibitors currently being developed for clinical use may be useful therapy for tumors such as NB in which endogenous cdk inhibitors are defective.
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PMID:P21Waf1/Cip1 dysfunction in neuroblastoma: a novel mechanism of attenuating G0-G1 cell cycle arrest. 1283 82

Bone morphogenetic proteins (BMPs) play an essential role in cell fate determination. In this study, we found that BMP2 treatment resulted in growth arrest and differentiation in human neuroblastoma-derived cell lines, SH-SY5Y and RTBM1. Within 30min of BMP2 exposure, phosphorylation of Smad1/5 was observed in these cell lines. In RTBM1 cells, BMP2-induced differentiation was accompanied by a significant decrease in the expression level of DAN, an antagonist of BMP in frog embryos. Immunoblot analysis revealed that BMP2 treatment caused a down-regulation of p53 family members and hence of cyclin-dependent kinase inhibitor p21(WAF1). We found a significant accumulation of p27(KIP1) in response to BMP2, whereas the expression level of Skp2, which is required for ubiquitin-dependent p27(KIP1) degradation, was decreased during this differentiation process. Our results suggest that p27(KIP1) contributes to the BMP-induced growth arrest and neuronal differentiation of neuroblastoma, and BMP treatment might provide a new therapeutic strategy.
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PMID:Accumulation of p27 KIP1 is associated with BMP2-induced growth arrest and neuronal differentiation of human neuroblastoma-derived cell lines. 1285 1

SH-SY5Y neuroblastoma cells were cultured for up to three serial passages in the presence of the copper chelator triethylene tetramine (Trien). The copper-depleted neuroblastoma cell line obtained showed decreased activities of the copper enzymes Cu, Zn super-oxide dismutase and cytochrome c oxidase with concomitant increases in reactive oxygen species. Mitochondrial antioxidants (Mn superoxide dismutase and Bcl-2)were up-regulated. Overexpression and activation of p53 were early responses, leading to an increase in p21. Eventually, copper-depleted cells detached from the monolayer and underwent apoptosis. Activation of upstream caspase-9, but not caspase-8, suggested that apoptosis proceeds via a mitochondrial pathway, followed by caspase-3 activation. The addition of copper sulfate to the copper-depleted cells restored copper enzymes, normalized antioxidant levels and improved cell viability. We conclude that prolonged copper starvation in these replicating cells leads to mitochondrial damage and oxidative stress and ultimately, apoptosis.
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PMID:Prolonged copper depletion induces expression of antioxidants and triggers apoptosis in SH-SY5Y neuroblastoma cells. 1451 38

Phenformin is a biguanide that has been largely used in the past for its anti-diabetic activity. A large body of evidence suggests additional effects of phenformin including antitumoral activity in different animal models in vivo. Thus, the present study has been conducted in order to elucidate possible mechanisms involved in the antitumoral effects of phenformin. In various tumoral cell lines (SH-SY5Y neuroblastoma and LNCaP prostate adenocarcinoma cells), increasing concentrations of phenformin (50-500 microM) induced a concentration-dependent inhibition of cell proliferation. This effect was not dependent on the ability of the drug to reduce glucose levels and was accompanied by induction of apoptotic cell death as measured by cytofluorometric analysis. In addition, a short-time incubation of SH-SY5Y cells with phenformin induced enhanced and transient expression of the cell cycle inhibitor p21 suggesting that phenformin causes inhibition of cell cycle progression prior to induction of apoptosis. These results demonstrate an activity at the cellular level of phenformin that supports its antitumoral effect observed in vivo.
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PMID:Effects of phenformin on the proliferation of human tumor cell lines. 1462 34

Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and betaA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH-SY5Y cell line, agonists for A1R led to a dose-dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK-dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD.
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PMID:A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation. 1465 50

p73, the first p53 gene homologue, encodes an array of p73 proteins including p73 alpha full-length (TAp73 alpha) and amino-truncated isoforms (Delta Np73 alpha), two proteins with opposite biological functions. TAp73 alpha can induce tumor suppressive properties, while Delta Np73 alpha antagonizes p53 as well as TAp73 in a dominant-negative manner. In human malignant neuroblasts, p53 protein is wild-type but known to be excluded from the nucleus, therefore disabling its function as a tumor suppressor. The present study investigates whether there is a functional link between p73 isoforms and p53 in neuroblastoma. Experiments were performed on two neuroblastoma cell lines differing in their p53 status, e.g. wild-type p53 SH-5Y5Y cells and mutated p53 IGR-N-91 cells. Data indicate that (i) both TA- and Delta N-p73 alpha enhance p53 protein level in SH-SY5Y cells, whereas level remains unchanged in IGR-N-91 cells; (ii) only in SH-SY5Y cells does forced TAp73 alpha overexpression markedly induce nuclear accumulation of p53 protein; (iii) p21 protein expression is increased in both cell lines infected with TAp73, suggesting that, in IGR-N-91 cells, p21 is induced by p73 through a p53-independent pathway; (iv) in the SHSY5Y cell line, Btg2 expression is strongly enhanced in cells overexpressing TA, and to a lesser extent in cells overexpressing Delta N. Taken together our results suggest that TAp73 may restore p53 function in NB with wild-type nonfunctional p53, but not in NB with mutated p53.
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PMID:Differential response of p53 target genes to p73 overexpression in SH-SY5Y neuroblastoma cell line. 1467 79

Mutations of p53 are rare in primary and advanced neuroblastomas. The p53 gene was studied in a TGW cell line established from a TNB1 xenograft, derived from metastasized neuroblastoma. The p53 protein level in TGW was elevated at baseline. Treatment with doxorubicin to induce genotoxic stress neither altered the p53 protein level nor induced p21 protein within 24 hours. DNA sequencing analysis revealed a novel triplet deletion mutation at codon 282 (R282del) of the p53 gene, a mutation also found in TNB1, indicating that the mutation occurred in the relapsed tumor. The mutant was incapable of transactivation and had no effect on the transactivational activity of the wild-type p53 gene product in reporter assays using a plasmid possessing a p53 responsive element of p21, bax or mdm2. These results suggest that the mutant p53R282del found in TGW is a non-functional mutant and has no dominant negative nature.
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PMID:A novel dysfunctional p53 mutation in the human neuroblastoma cell line TGW. 1469 15

Mycophenolic acid (MPA) specifically inhibits inosine-5'-monophosphate dehydrogenase, the first committed step toward GMP biosynthesis. In its morpholinoethyl ester pro-drug form it is one of the most promising immunosuppressive drugs recently developed. The aim of the present study was to investigate the in vitro effects of MPA, at concentrations readily attainable during immunosuppressive therapy, on 3 human neuroblastoma cell lines (LAN5, SHEP and IMR32). Mycophenolic acid (0.1-10 microM) caused a decrease of intracellular levels of guanine nucleotides, a G(1) arrest and a time- and dose-dependent death by apoptosis. These effects, associated with an up-regulation of p53, p21 and bax, a shuttling of p53 protein into the nucleus and a down-regulation of bcl-2, survivin and p27 protein, were reversed by the simultaneous addition of guanine or guanosine and were more evident using nondialysed serum containing hypoxanthine. These results suggest that in neuroblastoma cell lines clinically attainable concentrations of mycophenolic acid deplete guanine nucleotide pools triggering G(1) arrest and apoptosis through p53-mediated pathways, indicating a potential role of its morpholinoethyl ester pro-drug in the management of patients with neuroectodermal tumors.
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PMID:Guanine nucleotide depletion triggers cell cycle arrest and apoptosis in human neuroblastoma cell lines. 1535 52

The present study was undertaken to verify whether induction of senescence could be sufficient to reverse drug resistance and, if so, to determine the underlying mechanism(s). Our findings indicated that cotreatment of drug-resistant neuroblastoma cells with doxorubicin, at sublethal concentrations, in combination with the pan-caspase inhibitor, Q-VD-OPH, elicited a strong reduction of cell viability that occurred in a caspase-independent manner. This was accompanied by the appearance of a senescence phenotype, as evidenced by increased p21/WAF1 expression and senescence-associated beta-galactosidase activity. Experiments using specific inhibitors of major cellular proteases other than caspases have shown that inhibition of cathepsin L, but not proteasome or cathepsin B, was responsible for the senescence-initiated reversal of drug resistance. This phenomenon appeared to be general because it was valid for other drugs and drug-resistant cell lines. A nonchemical approach, through cell transfection with cathepsin L small interfering RNA, also strongly reversed drug resistance. Further investigation of the underlying mechanism revealed that cathepsin L inhibition resulted in the alteration of intracellular drug distribution. In addition, in vitro experiments have demonstrated that p21/WAF1 is a substrate for cathepsin L, suggesting that inhibition of this enzyme may result in p21/WAF1 stabilization and its increased accumulation. All together, these findings suggest that cathepsin L inhibition in drug-resistant cells facilitates induction of senescence and reversal of drug resistance. This may represent the basis for a novel function of cathepsin L as a cell survival molecule responsible for initiation of resistance to chemotherapy.
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PMID:Senescence-initiated reversal of drug resistance: specific role of cathepsin L. 1499 39


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