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)

Survivin inhibits apoptosis during development and carcinogenesis and is absent in differentiated cells. To determine whether survivin inhibition induces cell death in neural tumor cells, survivin antisense oligonucleotides (SAO) were administered to a human neuroblastoma (MSN) and an oligodendroglioma (TC620) resulting in a dose-dependent reduction in survivin protein. Although 74% of the SAO-treated MSN cells were trypan blue(+), PARP cleavage or activated caspase-3 was not observed. However nuclear translocation of AIF occurred and XIAP increased dramatically. Co-administration of z-Val-Ala-Asp(OMe)-fluoromethyl ketone (zVAD-fmk) with SAO did not inhibit cell death suggesting a caspase-independent mechanism of cell death. Propidium iodide (PI) staining revealed multiple large macronuclei with no apoptotic bodies supporting a role for survivin in cell division. By contrast, while 70% of the SAO-treated TC620 cells were trypan blue(+), PARP was cleaved, cells were TUNEL(+) and PI-staining revealed macronuclei and numerous apoptotic bodies. Co-treatment of the TC620 cells with SAO and zVAD-fmk blocked cell death. While no macronuclei or apoptotic bodies were observed there was a two-fold increase in metaphase cells. Our results suggest that survivin inhibition decreases the viability of human neural tumor cells and as a result of mitotic catastrophe, cell death can be initiated by either a classic apoptotic mechanism or a caspase-independent mechanism.
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PMID:Survivin inhibition induces human neural tumor cell death through caspase-independent and -dependent pathways. 1167 71

Primary or acquired resistance to current treatment protocols remains a major concern in clinical oncology and may be caused by defects in apoptosis programs. Since recent data suggest that TRAIL can bypass apoptosis resistance caused by Bcl-2, we further investigated the role of Bcl-2 in TRAIL-induced apoptosis. Here we report that overexpression of Bcl-2 conferred protection against TRAIL in neuroblastoma, glioblastoma or breast carcinoma cell lines. Bcl-2 overexpression reduced TRAIL-induced cleavage of caspase-8 and Bid indicating that caspase-8 was activated upstream and also downstream of mitochondria in a feedback amplification loop. Importantly, Bcl-2 blocked cleavage of caspases-9, -7 and -3 into active subunits and cleavage of the caspase substrates DFF45 or PARP. Also, Bcl-2 blocked cleavage of XIAP and overexpression of XIAP conferred resistance against TRAIL indicating that apoptosis was also amplified through a feedforward loop between caspases and XIAP. In contrast, in SKW lymphoblastoid cells, TRAIL-induced activation of caspase-8 directly translated into full activation of caspases, cleavage of XIAP, DFF45 or PARP and apoptosis independent of Bcl-2 overexpression, although Bcl-2 similarly inhibited loss of mitochondrial membrane potential and the release of cytochrome c, AIF and Smac from mitochondria in all cell types. By demonstrating a cell type dependent regulation of the TRAIL signaling pathway at different level, e.g. by Bcl-2 and by XIAP, these findings may have important clinical implication. Thus, strategies targeting the molecular basis of resistance towards TRAIL may be necessary in some tumors for cancer therapy with TRAIL.
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PMID:Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. 1194 12

XIAP (X chromosome-linked inhibitor of apoptosis protein) has been shown to inhibit cell death in a variety of cells. XIAP binds to active caspases, but XIAP also has a carboxy-terminal RING domain that can regulate cell death via protein degradation. Here we have studied the function of full-length and RING-deleted XIAP in mouse sympathetic neurons microinjected with expression plasmids and in neuroblastoma cells stably overexpressing these proteins. Both full-length and RING-deleted XIAP-protected sympathetic neurons against death induced by nerve growth factor (NGF) withdrawal to about the same extent. However, the two proteins were differentially localized in transfected neurons, with RING-deleted XIAP present in the cytoplasm and full-length XIAP found mostly in cytoplasmic protein aggregates, as revealed by transmission electron microscopy. The occurrence of these aggregates was blocked by lactacystin, a proteasome inhibitor. In neuroblastoma cells, RING-deleted XIAP protected against death induced by staurosporine, thapsigargin, or serum withdrawal, whereas full-length XIAP was without effect. Full-length, but not RING-deleted, XIAP was degraded and ubiquitinated in the neuroblastoma cells. The results show that the presence of the RING domain differentially affected the neuroprotective ability of XIAP in sensory neurons and neuroblastoma cells. The RING domain was essentially required for the proteasomal association of XIAP and for its ubiquitination.
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PMID:Regulation of sympathetic neuron and neuroblastoma cell death by XIAP and its association with proteasomes in neural cells. 1269 33

Recent observations suggest that amyloid-beta (Abeta), a major constituent of senile plaques, induces apoptosis in cultured neuronal cells. However, the concentration of Abeta that leads to neuronal cell death is much higher (10-25 microM) than that in the cerebrospinal fluid of normal controls or AD patients (nM order). As reported here, we found that subtoxic concentrations (100-500 nM) of Abeta(1-42) can down-regulate the expression of the X-linked inhibitor of apoptosis (XIAP) in human SH-SY5Y neuroblastoma cells, and that vulnerability to oxidative stress caused by Abeta(1-42) is attenuated by over-expression of XIAP. These results suggest that down-regulation of XIAP expression in response to subtoxic, more physiological concentrations (100-500 nM) of Abeta(1-42) increases vulnerability to oxidative stress.
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PMID:Amyloid-beta down-regulates XIAP expression in human SH-SY5Y neuroblastoma cells. 1507 29

Neuroblastoma (NB) is a childhood neoplasm which heterogeneous behavior can be explained by differential regulation of apoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces rapid apoptosis in most tumor cells and thus represents a promising anticancer agent. We have reported silencing of caspase-8 expression in highly malignant NB cells as a possible mechanism of resistance to TRAIL-induced apoptosis. To explore the particular contribution of caspase-8 in such resistance, retroviral-mediated stable caspase-8 expression was induced in the IGR-N91 cells. As a result, sensitivity to TRAIL was fully restored in the caspase-8-complemented cells. TRAIL-induced cell death could be further enhanced by cotreatment of IGR-N91-C8 and SH-EP cells with cycloheximide or subtoxic concentrations of chemotherapeutic drugs in a caspase-dependent manner. Sensitization to TRAIL involved enhanced death receptor DR5 expression, activation of Bid and the complete caspases cascade. Interestingly, combined treatments also enhanced the cleavage-mediated inactivation of antiapoptotic molecules, XIAP, Bcl-x(L) and RIP. Our results show that restoration of active caspase-8 expression in a caspase-8-deficient NB cell line is necessary and sufficient to fully restore TRAIL sensitivity. Moreover, the synergistic effect of drugs and TRAIL results from activation of the caspase cascade via a mitochondrial pathway-mediated amplification loop and from the inactivation of apoptosis inhibitors.
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PMID:Drug-mediated sensitization to TRAIL-induced apoptosis in caspase-8-complemented neuroblastoma cells proceeds via activation of intrinsic and extrinsic pathways and caspase-dependent cleavage of XIAP, Bcl-xL and RIP. 1509 81

Neuroblastoma is a pediatric solid tumor with high morbidity and mortality in association with particular high-risk biological and clinical features (such as MYCN proto-oncogene amplification or advanced tumor stage). Such high-risk neuroblastomas may be initially responsive to cytoreductive therapies, yet the majority will ultimately demonstrate de novo or acquired chemoresistance leading to tumor progression and death. Insight into the genetic alterations responsible for these phenotypes are beginning to be gained, and subversion of inherent programmed cell death pathways is a common theme. Intact apoptosis pathways protect cells against neoplastic transformation and provide the mechanisms by which cytotoxic agents exert their effects. When these pathways are abolished through alterations in the cell death machinery, they complement deregulated oncogenes to promote tumor initiation and therapy resistance. Currently, therapeutic intensity for high-risk neuroblastoma has been advanced to near-tolerance with only modest gains in survival, and it is likely that further improvements in outcome will require innovative approaches that target key regulatory pathways that potentiate currently available therapies. Efforts to abrogate the cancer cell 'survival bias' engendered by alterations in death pathways are now a major focus in experimental cancer therapeutics, and their application to the problem of high-risk neuroblastoma form the basis of this review. These include agents that activate death receptors (TRAIL-agonists) or restore DISC competency (CDDO, DNA methyltransferase and HDAC inhibitors); reduce pro-survival Bcl2 homologues (Oblimersen sodium [AS-Bcl2], AS-Mcl1) or deliver a pro-apoptotic BH3 protein burden (BH3 peptides, gossypol, ABT737); or repress IAPs (Smac/Diablo peptides, AS-XIAP, AS-Survivin). As our knowledge of apoptosis dysregulation in neuroblastoma evolves, the possibilities for pro-apoptotic therapeutics seems not only promising, but a realistic adjunct to conventional treatments.
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PMID:Targeting programmed cell death pathways with experimental therapeutics: opportunities in high-risk neuroblastoma. 1592 59

While second mitochondria derived activator of caspase (Smac) has been described to sensitize for apoptosis, its effect on cell viability in the absence of apoptotic stimuli has remained unclear. Here, we report that Smac inhibits clonogenic tumor growth by blocking random migration and proliferation and by enhancing apoptosis in a cell density and cell type dependent manner in SH-EP neuroblastoma cells. Inhibition of clonogenic survival by overexpression of full-length or processed Smac strictly depended on low cell density, and was reversible by replatement at high density. We discovered that Smac inhibits cell motility and random migration at low cell density. In addition, Smac enhanced apoptosis and inhibited protein, but not mRNA expression of XIAP, survivin and other short-lived proteins (FLIP, p21), indicating that Smac may globally inhibit protein expression. Also, Smac inhibited proliferation and increased polynucleation with no evidence for polyploidy, cell cycle arrest or senescence indicating that Smac impaired cell division. Interestingly, inhibition of clonogenic capacity by Smac occurred independent of its apoptosis promoting activity. By demonstrating that Smac restrains clonogenic tumor growth, our findings may have important implications for control of tumor growth and/or its metastatic spread. Thus, Smac agonists may be useful in cancer therapy, for example, for tumor control in minimal residual disease. Oncogene (2005) 24, 7190-7202. doi:10.1038/sj.onc.1208876; published online 8 August 2005.
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PMID:Inhibition of clonogenic tumor growth: a novel function of Smac contributing to its antitumor activity. 1609 52

This study is to explore the inhibitory effect of methyl jasmonate on cell proliferation and expression of XIAP and survivin of human neuroblastoma cell line BE(2)-C. After cultivation of 1 - 2 mmol x L(-1) jasmonates with BE (2) -C cells for 6 - 24 h, the growth inhibiting rates of BE (2) -C cells were studied by MTT colorimetry. Cell proliferation was detected by colony formation assay. Cell cycle phases were assayed by propidium iodide staining flow cytometery. Cell apoptosis was inspected by acridine orange-ethidium bromide fluorescent staining, Hoechst 33258 fluorescent staining, and Annexin V-FITC and propidium iodide staining flow cytometry. Expressions of cyclin D1, XIAP and survivin were determined by RT-PCR and real-time RT-PCR. Methyl jasmonate inhibited the growth of BE(2)-C cells in a dose- and time-dependent manner. After addition of 1, 1.5 and 2 mmol x L(-1) of methyl jasmonate for 24 h, the inhibiting rates of cell growth reached 20.6% - 85.5% (P < 0.01), and the IC50 was 1.35 mmol x L(-1). The cell cycles were arrested at S phase. A part of cells presented the characteristic morphological changes of apoptosis. The early apoptotic rates were 13.51%, 17.32%, 24.59% (P < 0.01) and the cell death rates were 29.36% , 54.73% , 75.52% (P < 0.01), respectively. The expression of XIAP and survivin mRNA were downregulated by 18.5% - 68.9% , 22.4% - 48.7% (P < 0.05), respectively, without change in that of cyclin D1. The results indicated that methyl jasmonate could significantly inhibit the growth of BE(2) -C cells through inducing cell cycle arrest and apoptosis, downregulating the expression of XIAP and survivin might be one of its molecular mechanisms of action.
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PMID:[Methyl jasmonate induces apoptosis of human neuroblastoma cell line BE(2) -C and its mechanism]. 1882 59

Radiotherapy has been used as an adjunctive local-control modality for high-risk neuroblastoma. However, relapse due to radioresistance affects the success of radiotherapy. Ascertaining the fractionated radiation (FIR) modulated molecular targets is imperative in targeted molecular therapy. Accordingly, we investigated the (i) expression of genes representing six functional pathways; (ii) NFkappaB DNA-binding activity and (iii) expression of radioresponsive molecules after single dose (10 Gy) radiation (SDR) and FIR (2 Gy x 5) in human neuroblastoma cells. Alterations in gene expression were analyzed using QPCR-profiling, NFkappaB activity using electrophoretic mobility shift assay (EMSA) and pIkappaBalpha using immunoblotting. Modulations in TNFalpha, IL-1alpha, pAKT, IAP1, IAP2, XIAP, survivin, MnSOD, BID, Bak, MyD88 and Vegfc were determined using quantitative real-time PCR (Q-PCR) and immunoblotting. Compared to SDR, FIR significantly induced the expression of 25 genes and completely suppressed another 30 genes. Furthermore, FIR induced NFkappaB-DNA-binding activity and IkappaBalpha phosphorylation. Similarly, we observed an induced expression of IAP1, IAP2, XIAP, Survivin, IL-1alpha, MnSOD, Bid, Bak, MyD88, TNFalpha and pAKT in cells exposed to FIR. The results of the study clearly show distinct differences in the molecular response of cells between SDR and FIR. We identified several potential targets confining to NFkappaB signaling cascade that may affect radio-resistance after FIR.
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PMID:NFkappaB signaling related molecular alterations in human neuroblastoma cells after fractionated irradiation. 1943 49

Mutations in the superoxide dismutase 1 (SOD1) gene are linked to glutamate excitotoxicity in familial amyotrophic lateral sclerosis (fALS), but the underlying mechanism remains unclear. We investigated whether nuclear factor-kappaB (NF-kappaB) activation is involved in glutamate excitotoxicity by using motor neuron-neuroblastoma hybrid cells that expressed a mutant (G93A) SOD1 (mtSOD1) or wild-type SOD1 (wtSOD1). MtSOD1 cells were more vulnerable to glutamate excitotoxicity than wtSOD1 cells and showed higher NF-kappaB activity, higher nuclear cRel expression, and lower nuclear RelA expression under basal conditions. Glutamate treatment increased NF-kappaB activation along with nuclear expressions of RelA and cRel in wtSOD1 cells but induced only weak nuclear RelA expression in mtSOD1 cells. Suppression of NF-kappaB activation using transfection of the superrepressive mutant form of IkappaBalpha (mIkappaBalpha) inhibited nuclear RelA expression in both types of SOD1 cells, which increased glutamate excitotoxicity in wtSOD1 cells but not in mtSOD1 cells. Furthermore, immunohistochemistry confirmed stronger RelA immunoreactivity in the nuclei of motor neurons of spinal cord in wild-type SOD1 transgenic mice than in those in SOD1 G93A transgenic mice. In addition, we found that glutamate treatment decreased XIAP expression and increased caspase-3 activity in mtSOD1 cells and mIkappaBalpha-overexpressing wtSOD1 cells. Our results suggest that glutamate excitotoxicity in motor neurons of SOD1-linked fALS is attributable, at least in part, to the impairment of IkappaBalpha-dependent RelA activation and subsequent apoptosis mediated by XIAP inhibition and caspase-3 activation.
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PMID:Impairment of nuclear factor-kappaB activation increased glutamate excitotoxicity in a motoneuron-neuroblastoma hybrid cell line expressing mutant (G93A) Cu/Zn-superoxide dismutase. 2062 31


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