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)

There is growing evidence that apoptotic mechanisms underlie the neurodegeneration leading to Parkinson's disease. 1-Methyl-4-phenylpyridinium ion (MPP(+)), the active metabolite of the parkinsonism-inducing drug MPTP, induced apoptosis in cultures of human SH-SY5Y neuroblastoma cells. Nuclear fragmentation, DNA laddering, and a 20% decrease in viability were seen after a 4-day incubation with 5 microM MPP(+). Cell viability decreased by 40% at 100 microM MPP(+), but the degree of apoptosis was not correlatively increased. The MPP(+)-induced apoptosis was completely prevented by the broad caspase inhibitor zVAD.fmk but not by the caspase-8 inhibitor IETD.fmk. Furthermore, MPP(+) had no effect on the levels of Fas or Fas-L, suggesting lack of activation of the Fas-L/Fas/caspase-8 pathway of apoptosis. There was no evidence of mitochondrial dysfunction at 5 microM MPP(+): No differences were seen in transmembrane potential or in cytochrome c release from controls. At 100 microM MPP(+), the mitochondrial potential decreased, and cytoplasmic cytochrome c and caspase-9 activation increased slightly. At both low and high concentrations of MPP(+), VDVADase and DEVDase activities increased. We conclude that MPP(+) can induce caspase-mediated apoptosis, which is prevented by caspase inhibition, at concentrations lower than those needed to trigger mitochondrial dysfunction and closer to those found in the brains of MPTP-treated animals.
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PMID:Low concentrations of 1-methyl-4-phenylpyridinium ion induce caspase-mediated apoptosis in human SH-SY5Y neuroblastoma cells. 1122 17

Disruption of apoptotic pathways may be involved in tumor formation, regression, and treatment resistance of neuroblastoma (NB). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in cancer cell lines, whereas normal cells are not sensitive to TRAIL-mediated apoptosis. In this study we analyzed the expression and function of TRAIL and its agonistic and antagonistic receptors as well as expression of cellular FLICE-like inhibitory protein and caspase-2, -3, -8, -9, and -10 in 18 NB cell lines. Semiquantitative RT-PCR revealed that TRAIL-R2 and TRAIL-R3 are the main TRAIL-receptors used by NB cells. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cellular FLICE-like inhibitory protein. Surprisingly, caspase-8 and caspase-10 mRNA expression was detected in only 5 of 18 NB cell lines. Interestingly, only these five NB cell lines were susceptible to TRAIL-induced apoptosis in a time- and dose-dependent manner. Treatment with 5-aza-2'-deoxycytidine restored mRNA and protein expression of caspase-8 and TRAIL sensitivity of resistant cell lines, suggesting that gene methylation is involved in caspase inactivation. The TRAIL system seems to be functional in NB cells expressing caspase-8 and/or caspase-10. Because many cytotoxic drugs induce caspase-dependent apoptosis, failure to express caspase-8 and/or caspase-10 might be an important mechanism of resistance to chemotherapy in NB.
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PMID:Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. 1124 27

Fas-mediated apoptosis proceeds though mitochondria-dependent or -independent pathways and is deficient in drug-resistant cells. Neuroblastoma, a common pediatric malignancy, often develops drug-resistance and has a silenced caspase 8 (FLICE) gene, which has been associated with Fas- and drug-resistance. We report that besides caspase 8, which was absent in approximately one-third of 26 neuroblastoma cases in this study, other proteins such as bcl-2 and FLICE-inhibitory protein (FLIP), are equally important in conferring Fas-resistance to neuroblastoma cells. Both bcl-2 and FLIP were frequently expressed in neuroblastoma tissues. Our in vitro studies showed that FLIP was recruited to the death-inducing signaling complex and interfered with the recruitment of caspase 8 in neuroblastoma cells. bcl-2 inhibited the activation of the mitochondria; but it also lowered the free cytoplasmic levels of caspase 8 by binding and sequestering it, thus acting through a novel antiapoptotic mechanism upstream of the mitochondria. In vitro down-regulation of bcl-2 with antisense oligonucleotides allowed the release of cytochrome c from mitochondria and the activation of caspases 8 and 3 upon Fas activation as well as sensitized neuroblastoma cells to Fas-mediated apoptosis. Down-regulation of FLIP had only a modest apoptotic effect because of the coexistent mitochondrial block. However, combined treatment with bcl-2 and FLIP antisense oligonucleotides had a statistically significant synergistic effect reversing Fas-resistance in neuroblastoma cells in vitro. These data indicate that Fas-mediated apoptosis in neuroblastoma cells is mitochondria-dependent and inhibited both at the mitochondrial level and at the level of caspase 8 activation. Thus, gene-targeting therapies for bcl-2 and FLIP may reverse Fas-resistance and prove useful in the treatment of drug-resistant neuroblastomas.
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PMID:Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2. 1140 64

We previously reported a high incidence of loss of heterozygosity (LOH) on chromosome 2q33 in neuroblastoma (NB), observed in various types of human cancers including lung cancer, head and neck cancer and follicular thyroid carcinoma. To better elucidate the role of chromosome 2q aberrations in NB, we examined common allelic imbalance (AI) regions on chromosome 2q in 82 NB patients using 10 polymorphic microsatellite markers. AI on 2q was detected in 26 (32%) of 82 NB cases. There was a distinct common AI region between the D2S115 and D2S307 markers on 2q33. The distance between these markers was about 2.0 cM. Recently, the caspase 8 and caspase 10 genes, both of which encode cystein protease, were mapped to chromosome 2q33. Since the common AI region on 2q33 includes the caspase 8 and caspase 10 genes, the alterations of these genes were examined further. Absent or reduced expression of caspase 8 and caspase 10 were found in 19 (70%) of 27 and two (7%) of 27 NB cell lines by reverse transcription-polymerase chain reaction, respectively. A missense mutation was detected at codon 96, GCT (Alanine) to GTT (Valine), of the caspase 8 gene in one of the NB cell lines lacking caspase 8 expression. Thirteen (68%) of 19 cell lines lacking caspase 8 expression displayed methylation of the CpG island of the caspase 8 gene, whereas only one (13%) of eight cell lines with caspase 8 expression showed caspase 8 methylation (P=0.031). Furthermore, there was a significant association between AI at 2q33 and loss of caspase 8 expression (P=0.026). These results indicated that there was a tumor suppressor gene in the common AI region on chromosome 2q33 involved in the pathogenesis of a subset of NB. It is possible that the caspase 8 gene is one of the candidate tumor suppressor genes for NB and inactivation of this gene plays an important role in the tumorigenesis of NB through mainly its methylation.
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PMID:Allelic imbalance on chromosome 2q and alterations of the caspase 8 gene in neuroblastoma. 1146 26

In this work we have investigated the molecular basis of the neuronal damage induced by the prion peptide by searching for a surface receptor whose activation could be the first step of a cascade of events responsible for cell death. By using a human neuroblastoma cell line lacking all the neurotrophin receptors and derived clones expressing the full-length or truncated forms of the low affinity neurotrophin receptor (p75(NTR)), we have been able to demonstrate that the neuronal death induced by the prion protein fragment PrP-(106-126) is an active process mediated by a) the binding of the peptide to the extracellular region of p75(NTR), b) the signaling function of the intracytoplasmic region of the receptor, and c) the activation of caspase-8 and the production of oxidant species.
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PMID:Neurotrophin p75 receptor is involved in neuronal damage by prion peptide-(106-126). 1148 11

Neuroblastomas that overexpress N-Myc due to amplification of the MYCN oncogene are aggressive tumors that become very resistant to treatment by chemotherapy and irradiation. to identify tumor suppressor genes in this group of neuroblastomas we analyzed the expression and function of both apoptosis-related cell cycle regulatory genes in cell lines and patient tumor samples. We found that in a high percentage of neuroblastoma cell lines and patient samples with amplified MYCN, caspase-8 mRNA is not expressed. The caspase-8 gene, CASP8, was deleted or silenced by methylation in the neuroblastoma cell lines while methylation of its promoter region was the predominant mechanism for its inactivation in the patient tumor samples. Reintroduction of caspase-8 into the neuroblastoma cell lines resensitized these cells to drug-induced and survival factor dependent apoptosis. Subsequently others have also shown that caspase-8 is silenced by methylation in neuroblastoma and peripheral neural ectodermal tumors, and that the caspase-9 regulator Apaf-1 is silenced by methylation in melanoma cell lines and patient samples. We conclude that caspase-8 acts as a tumor suppressor gene in neuroblastomas, that its silencing provides a permissive environment for MYCN gene amplification once the tumors are treated with chemotherapeutic drugs/irradiation, and that expression of this gene in these tumor cells may be of clinical benefit. We also discuss the possible significance of the neural crest cell progenitor cell origin and the silencing of important apoptotic regulators via methylation in both neuroblastoma and melanoma tumors.
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PMID:Aggressive childhood neuroblastomas do not express caspase-8: an important component of programmed cell death. 1151 73

Resistance of tumors to treatment with cytotoxic drugs, irradiation or immunotherapy may be due to disrupted apoptosis programs. Here, we report in a variety of different tumor cells including Ewing tumor, neuroblastoma, malignant brain tumors and melanoma that caspase-8 expression acts as a key determinant of sensitivity for apoptosis induced by death-inducing ligands or cytotoxic drugs. In tumor cell lines resistant to TRAIL, anti-CD95 or TNFalpha, caspase-8 protein and mRNA expression was decreased or absent without caspase-8 gene loss. Methylation-specific PCR revealed hypermethylation of caspase-8 regulatory sequences in cells with impaired caspase-8 expression. Treatment with the demethylation agent 5-Aza-2'-deoxycytidine (5-dAzaC) reversed hypermethylation of caspase-8 resulting in restoration of caspase-8 expression and recruitment and activation of caspase-8 at the CD95 DISC upon receptor cross-linking thereby sensitizing for death receptor-, and importantly, also for drug-induced apoptosis. Inhibition of caspase-8 activity also inhibited apoptosis sensitization by 5-dAzaC. Similar to demethylation, introduction of caspase-8 by gene transfer sensitized for apoptosis induction. Hypermethylation of caspase-8 was linked to reduced caspase-8 expression in different tumor cell lines in vitro and, most importantly, also in primary tumor samples. Thus, these findings indicate that re-expression of caspase-8, e.g. by demethylation or caspase-8 gene transfer, might be an effective strategy to restore sensitivity for chemotherapy- or death receptor-induced apoptosis in various tumors in vivo.
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PMID:Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. 1159 92

Neuroblastoma is the most common extracranial solid tumor of childhood. N-type neuroblastoma cells (represented by SH-SY5Y and IMR32 cell lines) are characterized by a neuronal phenotype. N-type cell lines are generally N-myc amplified, express the anti-apoptotic protein Bcl-2, and do not express caspase-8. The present study was designed to determine the mechanism by which N-type cells die in response to specific cytotoxic agents (such as cisplatin and doxorubicin) commonly used to treat this disease. We found that N-type cells were equally sensitive to cisplatin and doxorubicin. Yet death induced by cisplatin was inhibited by the nonselective caspase inhibitor z-Val-Ala-Asp-fluoromethylketone or the specific caspase-9 inhibitor N-acetyl-Leu-Glu-His-Asp-aldehyde, whereas in contrast, caspase inhibition did not prevent doxorubicin-induced death. Neither the reactive oxygen species nor the mitochondrial permeability transition appears to play an important role in this process. Doxorubicin induced NF-kappa B transcriptional activation in association with I-kappa B alpha degradation prior to loss of cell viability. Surprisingly, the antioxidant and NF-kappa B inhibitor pyrrolidine dithiocarbamate blocked doxorubicin-induced NF-kappa B transcriptional activation and provided profound protection against doxorubicin killing. Moreover, SH-SY5Y cells expressing a super-repressor form of I-kappa B were completely resistant to doxorubicin killing. Together these findings show that NF-kappa B activation mediates doxorubicin-induced cell death without evidence of caspase function and suggest that cisplatin and doxorubicin engage different death pathways to kill neuroblastoma cells.
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PMID:NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells. 1167 90

Important roles have been suggested for caspase-8, caspase-9 and Apaf-1 in controlling tumor development and their sensitivity to chemotherapeutic agents. Methylation and deletion of Apaf-1 and CASP8 results in the loss of their expression in melanoma and neuroblastoma, respectively, while CASP9 localization to 1p36.1 suggests it is a good candidate tumor suppressor. The status of CASP9 and Apaf-1 expression in numerous neuroblastoma cell lines with/without amplified MYCN and chromosome 1p36 loss-of-heterozygosity (LOH) was therefore examined to test the hypothesis that one or both of these genes are tumor suppressors in neuroblastoma. Although CASP9 is included in the region encompassing 1p36 LOH in all neuroblastoma cell lines examined, the remaining CASP9 allele(s) express a functional caspase-9 enzyme. Apaf-1 is also expressed in all neuroblastoma tumor cell lines examined. Thus, the CASP9 or Apaf-1 genes do not appear to function as tumor suppressors in MYCN amplified neuroblastomas. However, approximately 20% of the neuroblastoma cell lines with methylated CASP8 alleles are also highly resistant to staurosporine (STS)- and radiation-induced cell death, presumably because cytochrome c is not released from mitochondria. This suggests that a second, smaller sub-group of MYCN amplified neuroblastoma tumors exists with defect(s) in apoptotic signaling components upstream of caspase-9 and Apaf-1. Since no consistent differences in Bcl-2, Bcl-x(L) or Bax expression were seen in the STS- and radiation-resistant neuroblastomas, it suggests that a unique mitochondrial signaling factor(s) is responsible for the defect in cytochrome c release in this sub-group of tumors.
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PMID:Caspase-9 and Apaf-1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN. 1189 17

Glutamate and the NO donor, nitroprusside, synergistically induced the death of B50 cells from a rat CNS-derived neuroblastoma cell line. With low [nitroprusside] (10 microM) both nitroprusside and glutamate were required. Under these conditions, nuclei became pyknotic and caspases were activated. The activities of caspase-3 and caspase-6 (effector caspases) were higher than those of caspase-8 and caspase-9 (initiator caspases). The activation of all four caspases was inhibited by cyclosporin A, with the order of susceptibility caspase-8=caspase-9=caspase-6>caspase-3. To identify the possible locus of cyclosporin A action, we used an antisense oligodeoxynucleotide to suppress the level of cyclophilin-A to<5% of its control value. Cyclophilin-A suppression largely reproduced the inhibitory effects of cyclosporin A. These results provide the first indication that cyclophilin-A participates in the activation of the caspase cascade in neuronal cells, in particular in the form of cascade elicited by excitotoxic stimuli. It is concluded that neuroprotection by cyclosporin A against excitotoxin-induced apoptosis is, at least partly, due to inhibition of cyclophilin-A.
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PMID:Cyclophilin-A is involved in excitotoxin-induced caspase activation in rat neuronal B50 cells. 1190 43

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