Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Levels of vascular endothelial growth factor (VEGF) are regulated, in part, through activation of the phosphatidylinositol 3'-kinase/Akt pathway. Using pharmacologic inhibitors, we have examined the relative contributions of Akt and mammalian target of rapamycin (mTOR) signaling to VEGF production in neuroblastoma and rhabdomyosarcoma cells growing under normoxic (21% O(2)) or hypoxic (1% O(2)) conditions. Exogenous VEGF stimulated both Akt and extracellular signal-regulated kinase 1/2 phosphorylation in six of seven rhabdomyosarcoma cell lines but in only one of seven neuroblastoma cells, suggesting autocrine stimulation predominantly in rhabdomyosarcoma cell lines. In general, under normoxic conditions, neuroblastoma cells produced more VEGF (120-1,180 pg/10(6) cells/24 h) compared with rhabdomyosarcoma lines (0-200 pg/10(6) cells/24 h). Rapamycin, a selective inhibitor of mTOR, reduced VEGF production in rhabdomyosarcoma cells under normoxic conditions and partially suppressed hypoxia-driven increases in VEGF. However, it poorly inhibited VEGF production under either condition in the majority of neuroblastoma cell lines despite inhibition of mTOR signaling. Rapamycin failed to modulate levels of hypoxia-inducible factor 1alpha (HIF-1alpha) under normoxic conditions and modestly reduced hypoxia-driven increases in HIF-1alpha only in rhabdomyosarcoma cells. In contrast to rapamycin, inhibition of Akt by A-443654 completely blocked signaling to glycogen synthase kinase 3beta and had more dramatic effects on VEGF production. Notably, A-443654 significantly inhibited VEGF production in rapamycin-refractory neuroblastoma cell lines. Importantly, whereas combining A-443654 with rapamycin had variable effect on cell proliferation, the combination essentially blocked hypoxia-driven increases in VEGF in all cell lines examined, suggesting that dual blockade at different levels in the phosphatidylinositol 3'-kinase-initiated signaling pathway may be a reasonable strategy for preventing VEGF production in cancer cells derived from pediatric solid tumors. However, this will require formal testing in vivo using animal models of childhood cancer.
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PMID:Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors. 1748 38

In order to examine the neuroprotective effects of the alpha7 nicotinic receptor (nAChR) in relationship to the pathogenesis of Alzheimer's disease (AD), neuroblastoma (SH-SY5Y) cells were transfected with small interference RNAs (siRNAs) that targets specifically towards alpha7 nAChR or exposed to 20microM 3-[2,4-dimethoxybenzylidene] anabaseine (DMXB), a selective agonist of this same receptor. The levels of alpha7 nAChR mRNA and protein were measured by RT-PCR and Western blotting, respectively. The levels of the alpha-form of secreted amyloid precursor protein (alphaAPPs), total APP and the extracellular signal-regulated kinase 1/2 (ERK1/2) were also determined by Western blotting. SH-SY5Y cells transfected with siRNA or exposed to DMXB were then treated with 1microM Abeta(25-35), following which the levels of lipid peroxidation and rate of reduction of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] were characterized by utilizing spectrophotometric procedures. Compared to controls, SH-SY5Y cells transfected with siRNA expressed the decreases in the levels of alpha7 nAChR mRNA and protein by 81% and 69% lower levels, respectively; exhibited reduced levels of the alphaAPPs and ERK1/2 proteins; and demonstrated enhanced lipid peroxidation and a decreased rate of MTT reduction. In cells exposed to DMXB, the level of alpha7 nAChR protein was elevated by 23%, with no alteration in the content of the corresponding mRNA; the levels of the alphaAPPs and ERK1/2 proteins were increased. Inhibition of the expression of the alpha7 nAChR gene enhanced the toxicity exerted by Abeta, whereas stimulation of this receptor attenuated this toxicity exerted. These findings indicate that alpha7 nAChR may play a significant neuroprotective role by enhancing cleavage of APP by alpha-secretase, regulating signal transduction, improving antioxidant defenses and inhibiting the toxicity of Abeta, which is connected with the pathogenesis of AD.
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PMID:The consequences of reducing expression of the alpha7 nicotinic receptor by RNA interference and of stimulating its activity with an alpha7 agonist in SH-SY5Y cells indicate that this receptor plays a neuroprotective role in connection with the pathogenesis of Alzheimer's disease. 1749 9

Metastasis to the bone is seen in 56% of patients with neuroblastoma and contributes to morbidity and mortality. Using a murine model of bone invasion, we have reported previously that neuroblastoma cells invade the bone by activating osteoclasts. Here, we investigated the antitumoral and antiosteolytic activities of zoledronic acid, a bisphosphonate inhibitor of osteoclasts, in combination with cytotoxic chemotherapy in our model. We first show that zoledronic acid given at the same time (early prevention) or 2 weeks after tumor cell injection (late prevention) significantly prevented the formation of severe osteolytic lesions. It also prevented formation of these lesions when given 4 weeks after tumor cell injection (intervention) when combined with chemotherapy including cyclophosphamide and topotecan. The combination of zoledronic acid + cyclophosphamide/topotecan also significantly improved survival (P < 0.001). In mice treated with zoledronic acid, we observed a marked inhibition of osteoclasts inside the bone associated with a decrease in tumor cell proliferation and increase in tumor cell apoptosis. In vitro, zoledronic acid inhibited neuroblastoma cell proliferation and induced apoptosis, and these effects were significantly enhanced by the addition of 4-hydroxyperoxycyclophosphamide (4-HC). The proapoptotic effect of zoledronic acid and zoledronic acid in combination with 4-HC on tumor cells was associated with an increase in caspase-3 activity and a decrease in phosphorylated Bcl-2, Bcl-2, and Bcl-X(L) expression. Zoledronic acid inhibited the association of Ras with the plasma membrane and activation of c-Raf, Akt, and extracellular signal-regulated kinase 1/2. The data indicate that zoledronic acid, in addition to inhibiting osteoclasts, is active against tumor cells and suggest that zoledronic acid in combination with cytotoxic chemotherapy may be effective in children with neuroblastoma that has metastasized to the bone.
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PMID:The activity of zoledronic Acid on neuroblastoma bone metastasis involves inhibition of osteoclasts and tumor cell survival and proliferation. 1790 43

The purpose of the study was to investigate the antitumor effects of Isatin and the related mechanism. Human neuroblastoma cells (SH-SY5Y) were exposed to Isatin at different concentrations for 48 h. Apoptotic features were demonstrated by means of nuclei staining with Hoechst 33258 and flow cytometry with propidium iodide (PI). Expressions of Bcl-2, Bax and vascular endothelial growth factor (VEGF) mRNA were analyzed via RT-PCR. Expressions of Bcl-2, Bax proteins and phosphorylated extracellular signal regulated protein kinases (ERKs, p42/p44) were analyzed via Western blot. Activation of caspase-3 was assayed by flow cytometry with anti-active caspase-3-McAb-PE. VEGF protein was determined by ELISA kits. And the results showed that apoptosis of SH-SY5Y cells were induced by Isatin in a dose-dependent manner. Expressions of Bcl-2, VEGF mRNA and Bcl-2, VEGF proteins were down-regulated, while expressions of Bax mRNA and Bax protein were not changed obviously. Expression of phosphorylated ERKs decreased, but the level of activated caspase-3 increased after treatment of Isatin. These results suggest that Isatin promotes the apoptosis of neuroblastoma cells, therefore, it might be a potential candidate for the treatment of neuroblastoma.
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PMID:Antitumor effects of Isatin on human neuroblastoma cell line (SH-SY5Y) and the related mechanism. 1856 13

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta. Although understanding of the pathogenesis of PD remains incomplete, increasing evidence from human and animal studies has suggested that oxidative stress is an important mediator in its pathogenesis. Astaxanthin (Asx), a potent antioxidant, has been thought to provide health benefits by decreasing the risk of oxidative stress-related diseases. This study examined the protective effects of Asx on 6-hydroxydopamine (6-OHDA)-induced apoptosis in the human neuroblastoma cell line SH-SY5Y. Pre-treatment of SH-SY5Y cells with Asx suppressed 6-OHDA-induced apoptosis in a dose-dependent manner. In addition, Asx strikingly inhibited 6-OHDA-induced mitochondrial dysfunctions, including lowered membrane potential and the cleavage of caspase 9, caspase 3, and poly(ADP-ribose) polymerase. In western blot analysis, 6-OHDA activated p38 MAPK, c-jun NH(2)-terminal kinase 1/2, and extracellular signal-regulated kinase 1/2, while Asx blocked the phosphorylation of p38 MAPK but not c-jun NH(2)-terminal kinase 1/2 and extracellular signal-regulated kinase 1/2. Pharmacological approaches showed that the activation of p38 MAPK has a critical role in 6-OHDA-induced mitochondrial dysfunctions and apoptosis. Furthermore, Asx markedly abolished 6-OHDA-induced reactive oxygen species generation, which resulted in the blockade of p38 MAPK activation and apoptosis induced by 6-OHDA treatment. Taken together, the present results indicated that the protective effects of Asx on apoptosis in SH-SY5Y cells may be, at least in part, attributable to the its potent antioxidative ability.
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PMID:Protective effects of astaxanthin on 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells. 1901 78

Ras proteins are small guanosine triphosphatases involved in the regulation of important cellular functions such as proliferation, differentiation, and apoptosis. Understanding the intracellular trafficking of Ras proteins is crucial to identify novel Ras signaling platforms. In this study, we report that epidermal growth factor triggers Kirsten Ras (KRas) translocation onto endosomal membranes (independently of calmodulin and protein kinase C phosphorylation) through a clathrin-dependent pathway. From early endosomes, KRas but not Harvey Ras or neuroblastoma Ras is sorted and transported to late endosomes (LEs) and lysosomes. Using yellow fluorescent protein-Raf1 and the Raichu-KRas probe, we identified for the first time in vivo-active KRas on Rab7 LEs, eliciting a signal output through Raf1. On these LEs, we also identified the p14-MP1 scaffolding complex and activated extracellular signal-regulated kinase 1/2. Abrogation of lysosomal function leads to a sustained late endosomal mitogen-activated protein kinase signal output. Altogether, this study reveals novel aspects about KRas intracellular trafficking and signaling, shedding new light on the mechanisms controlling Ras regulation in the cell.
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PMID:A clathrin-dependent pathway leads to KRas signaling on late endosomes en route to lysosomes. 1928 94

Ginkgo biloba extract EGb761 has been shown to protect against beta-amyloid peptide (Abeta)-induced neurotoxicity but the specific mechanisms remain unclear. In the present study, effects of EGb761 and two of its constituents, quercetin and ginkgolide B, on the cytotoxic action of Abeta (1-42) were tested with human neuroblastoma SH-SY5Y cells. We found that EGb761 was able to block Abeta (1-42)-induced cell apoptosis, reactive oxygen species (ROS) accumulation, mitochondrial dysfunction and activation of c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling pathways. Both quercetin and ginkgolide B may be involved in the inhibitory effects of EGb761 on JNK, ERK1/2 and Akt signaling pathways. Ginkgolide B also helped to improve mitochondrial functions but quercetin failed to show this effect. Additional experiments suggest that, protective effects of EGb761 against Abeta toxicity may be associated with its antioxidant and platelet activating factor (PAF) antagonist activities. Quercetin but not ginkgolide B is one of the constituents responsible for the antioxidant action of EGb761. Both quercetin and ginkgolide B may be involved in the PAF antagonist activity of EGb761. Overall, actions of individual EGb761 components provide further insights into direct mechanisms underlying the neuroprotective effects of EGb761.
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PMID:Protective effects of Ginkgo biloba extract (EGb761) and its constituents quercetin and ginkgolide B against beta-amyloid peptide-induced toxicity in SH-SY5Y cells. 1946 78

Neuronal differentiation has evolved as an essential process even in the adult brain, once disturbed being associated with the pathogenesis of several psychiatric disorders. To study the effects of Raf kinase inhibitor protein (RKIP) on neuronal differentiation, we generated neuroblastoma cell lines overexpressing RKIP (RKIP(+)) and expressing RKIP-directed short hairpin RNA for downregulation of RKIP (RKIP(-)). During a 4-week time course of continuous differentiation by retinoic acid (RA), expression of neuronal and glial markers, intracellular cyclic adenosine monophosphate (cAMP) levels, protein kinase C (PKC) signal transduction to extracellular signal-regulated kinase 1/2 (ERK-1/2) and cellular morphology were investigated in relation to RKIP levels. RKIP(+) cells showed accelerated neurite outgrowth, formation of elaborated neuronal networks and increased neuronal marker expression both in RA-induced differentiation and to some extent even in non-RA-treated cells. RKIP(-) cells showed glial-like cell bodies and increased glial fibrillary acidic protein, suggesting a shift from neuronal to glial phenotype. With respect to differentiation-inducing signal pathways, PKC-mediated ERK-1/2 activation significantly correlated with RKIP levels. Furthermore, basal and forskolin-stimulated intracellular cAMP was potently increased in RKIP(+) cells versus controls. In conclusion, the conserved signal transduction modulator RKIP was shown to enhance several aspects of neuronal differentiation via enhanced crosstalk from PKC to ERK-1/2 and enhancement of G-protein-coupled receptor signaling.
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PMID:Raf kinase inhibitor protein enhances neuronal differentiation in human SH-SY5Y cells. 1995 95

The expression of cell differentiation and proliferation markers of canine neuroepithelial tumors was examined immunohistochemically to identify the histogenesis of these tumors. Astrocytomas (n = 4) consisted of cells positive for glial fibrillary acidic protein (GFAP) and nestin and a few cells positive for doublecortin (DCX). Immunoreactive cells for receptor tyrosine kinases (epidermal growth factor receptor and c-erbB2) and their downstream molecules (phospho-extracellular signal-regulated kinase 1/2 and phospho-Akt) were often detected in astrocytomas, especially in medium- and high-grade tumors. Gliomatosis cerebri (n = 3) consisted of cells positive for ionized calcium-binding adaptor molecule 1 and GFAP, including a minor population of cells positive for nestin, DCX, and beta III tubulin, suggesting their glial differentiation. In choroid plexus tumors (n = 4), most tumor cells were positive for cytokeratins AE1/AE3 and 18, and few were positive for GFAP. The majority of cells of oligodendrogliomas (n = 5) were DCX positive, but the tumors also contained minor populations of cells positive for GFAP, nestin, or beta III tubulin. Primitive neuroectodermal tumors (PNETs; n = 2) consisted of heterogeneous cell populations, and the tumor cells were positive for nestin, beta III tubulin, and DCX, suggesting glial and neuronal differentiation. The major population of neuroblastoma cells (n = 3) were positive for beta III tubulin and DCX, suggesting single neuronal differentiation. As for antiapoptotic cell death molecules, most tumor cells in the choroid plexus tumors, PNETs, and neuroblastomas were intensely positive for Bcl-2 and Bcl-xL, whereas those in gliomatosis cerebri were almost negative. In astrocytomas, Bcl-xL-positive cells predominated over Bcl-2-positive cells, but the opposite was observed in oligodendrogliomas. The immunohistochemical results were analyzed by hierarchical clustering, and the constructed dendrogram clearly indicated a novel position of oligodendrogliomas: the primitive glial and neuronal differentiation.
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PMID:Immunohistochemical characterization of canine neuroepithelial tumors. 2041 71

Neuroblastoma is a common solid tumor in children and its tumorigenicity is enhanced by the expression of survival pathways such as Akt and signal transducer and activator of transcription 3 (STAT3). Sorafenib is a multikinase inhibitor that also inhibits STAT3 signaling and induces apoptosis. In this study, we will examine the efficacy of sorafenib on a human neuroblastoma cell line (SK-N-AS) and also investigate its possible mechanisms. After cells reached 50-60% confluence, they were treated with various concentrations of sorafenib (0, 0.1, 1, 5, 10 and 20 microM) for different periods of time. The cell viability and apoptosis were determined by MTS colorimetric assay and TUNEL, respectively. Phosphorylation of Akt1/2/3 (p-Akt1/2/3), extracellular signal-regulated kinase 1/2 (p-ERK1/2), STAT3 (p-STAT3), and AMP-activated protein kinase alpha subunit (p-AMPKalpha) were determined with Western blot. The results indicate that as early as 2 hours post-treatment, cell viability was significantly decreased at 10 microM concentration. In 24 hours or longer treatment groups, sorafenib at 5 microM and above significantly decreased cell viability. TUNEL assay showed a significant increased of apoptosis in 5 and 20 microM treatment groups 24 hours after treatment. Western blots showed a decrease of p-ERK1/2, p-Akt1/2/3, p-STAT3, and p-AMPKalpha expression levels in various sorafenib treatment groups. Our results indicate that sorafenib significantly decreased cell viability and increased apoptosis in human neuroblastoma cell line in association with down-regulation of p-ERK1/2, p-Akt, p-STAT3 survival pathways. These data suggested potential clinical application of sorafenib in the treatment of neuroblastoma.
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PMID:Sorafenib downregulates ERK/Akt and STAT3 survival pathways and induces apoptosis in a human neuroblastoma cell line. 2049 Mar 31


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