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)

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Recently, we have shown that insulin-like growth factor-I and serum-derived growth factors stimulate VEGF expression in neuroblastoma cells via induction of hypoxia-inducible factor-1alpha (HIF-1alpha). Because another marker of poor prognosis in neuroblastoma tumors is high expression of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, TrkB, we sought to evaluate the involvement of BDNF and TrkB in the regulation of VEGF expression. VEGF mRNA levels in neuroblastoma cells cultured in serum-free media increased after 8 to 16 hours in BDNF. BDNF induced increases in VEGF and HIF-1alpha protein, whereas HIF-1beta levels were unaffected. BDNF induced a 2- to 4-fold increase in VEGF promoter activity, which could be abrogated if the hypoxia response element in the VEGF promoter was mutated. Transfection of HIF-1alpha small interfering RNA blocked BDNF-stimulated increases in VEGF promoter activity and VEGF protein expression. The BDNF-stimulated increases in HIF-1alpha and VEGF expression required TrkB tyrosine kinase activity and were completely blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. These data indicate that BDNF plays a role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal transduction pathways, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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PMID:Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. 1661 48

Choline kinase (ChoK) is a cytosolic enzyme present in various tissues, which catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is important for the generation of two major membrane phospholipids, phosphatidylcholine (PC) and sphingomyelin (SM) and subsequently for the cell division. ChoK plays a vital role in cell signaling pathways and regulation of cell growth along with PCho involved in malignant transformation through ras oncogenes in different cancers such as breast, lung, colon, prostate, neuroblastoma, hepatic lymphomas, meningiomas and diverse murine tumours. The Ras effectors serine/threonine kinase (Raf-1), the Ral-GDP dissociation stimulator (Ral-GDS) and the phosphatidylinositol 3-kinase (PI3K) are involved in the activation of ChoK during tumorigenesis. ChoK gene induction seems to be associated with certain cell stress or cell defense. Nowadays, RNAi appear to be one of the most promising routes in the cancer therapy. The anticancer potential of both stable expression of siRNAs and their high sequence specificity by RNAi mediated suppression of oncogenic ras in human pancreatic carcinoma, human melanomas and ovarian cancer has been observed. It has an important role in sequence specific post-transcriptional gene silencing mechanism. Presently, the crystal structure of Caenorhabditis elegans choline kinase A-2 (ChoKA-2) is available, which may be useful for comparative modeling of human ChoK and further modeling studies. The present review aims at the general overview of importance, expression, structure, progress in molecular modeling, active site analysis and inhibitors of ChoK. It also highlights the recent role of ChoK in various types of Ras-dependent and Ras-independent carcinogenesis.
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PMID:Choline kinase: an important target for cancer. 1671 78

Amplification of MYCN occurs commonly in neuroblastoma. We report that phosphatidylinositol 3-kinase (PI3K) inhibition in murine neuroblastoma (driven by a tyrosine hydroxylase-MYCN transgene) led to decreased tumor mass and decreased levels of Mycn protein without affecting levels of MYCN mRNA. Consistent with these observations, PI3K inhibition in MYCN-amplified human neuroblastoma cell lines resulted in decreased levels of Mycn protein without affecting levels of MYCN mRNA and caused decreased proliferation and increased apoptosis. To clarify the importance of Mycn as a target of broad-spectrum PI3K inhibitors, we transduced wild-type N-myc and N-myc mutants lacking glycogen synthase kinase 3beta phosphorylation sites into human neuroblastoma cells with no endogenous expression of myc. In contrast to wild-type N-myc, the phosphorylation-defective mutant proteins were stabilized and were resistant to the antiproliferative effects of PI3K inhibition. Our results show the importance of Mycn as a therapeutic target in established tumors in vivo, offer a mechanistic rationale to test PI3K inhibitors in MYCN-amplified neuroblastoma, and represent a therapeutic approach applicable to a broad range of cancers in which transcription factors are stabilized through a PI3K-dependent mechanism.
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PMID:Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. 1691 92

The actions of estradiol in the brain involve the interaction with growth factors, such as insulin-like growth factor-I (IGF-I). Many cells in the brain coexpress receptors for estradiol (ERs) and IGF-I (IGF-IR) and both factors interact to regulate neural function. Several studies have shown that there is an interaction of IGF-IR and ERs in neuroprotection. Neuroprotective effects of estradiol are blocked by the inhibition of IGF-IR signaling, while the neuroprotective effects of IGF-I are blocked by the inhibition of ER signaling. These findings suggest that the neuroprotective actions of estradiol and IGF-I after brain injury depend on the coactivation of both ERs and IGF-IR in neural cells. The relationship of ERalpha with IGF-IR through the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta (PI3K/Akt/GSK3) signaling pathway may represent the point of convergence used by estradiol and IGF-I to cooperatively promote neuroprotection. Administration of estradiol to ovariectomized rats results in the association of ERalpha with IGF-IR and with components of the PI3K/Akt/GSK3 signaling pathway and in the regulation of the activity of Akt and GSK3 in the brain. Conversely, IGF-I regulates ERalpha transcriptional activity in neuroblastoma cells and the PI3K/Akt/GSK3 signaling pathway is involved in this effect.
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PMID:Cross-talk between IGF-I and estradiol in the brain: focus on neuroprotection. 1712 77

The active form of 1,25-dihydroxyvitamin D(3) prevents neuronal damage in vitro and in vivo , however, it induces also hypercalcemia and hyperphosphatemia. Side-chain-modified analogues of 1,25-dihydroxyvitamin D(3), which show low calcemic activity, may be potentially useful in the treatment of some neurodegenerative diseases. Previously, we have found that PRI-2191 more potently than 1,25-dihydroxyvitamin D(3) protects human neuroblastoma (SH-SY5Y) cells against hydrogen-peroxide-induced toxicity. In the present study, we evaluated effects of two other 1,25-dihydroxyvitamin D(3) analogues - PRI-1890 and PRI-1901 on the neuronal degeneration in the same cell model. In line with the previous study, 24-h incubation with hydrogen peroxide (0.5 mM) was toxic to cells, as evidenced by an enhanced efflux of lactate dehydrogenase into the culture medium, and these effects were prevented by PRI-1890 and PRI-1901 at concentration of 5, 50 and 500 nM. Comparing the neuroprotective effects of secosteroids, we found that all three analogues were efficient at lower concentration than 1,25-dihydroxyvitamin D(3) and among them the PRI-2191 showed the most evident concentration-dependent effect. In the second part of this study, an involvement of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K), kinases which play a crucial role in neurodegenerative processes, in neuroprotective action of 1,25 dihydroxyvitamin D(3) and its the most potent analogue PRI-2191 has been investigated. The inhibitor of c-Jun N-terminal kinase (JNK)-MAPK (SP600125, 1 microM), inhibitor of p38-MAPK (SB-203580, 1 and 10 microM) and inhibitor of extracellular signal-regulated kinase (ERK)-MAPK (PD-98059, 15 and 30 microM) attenuated the hydrogen peroxide-induced toxicity. Moreover, PD-98059 (30 microM) enhanced neuroprotective effects of 1,25 dihydroxyvitamin D(3) but not that of PRI-2191. In contrast, the inhibitor of PI3-K (wortmannin, 10, 100 nM) did not affect hydrogen peroxide-induced cell damage itself, however, it significantly antagonized the effect of PRI-2191. On the other hand, wortmannin did not affect the neuroprotective effects of 1,25 dihydroxyvitamin D(3) This suggests that the activation of PI3-K/Akt signaling pathway plays an important role in the mechanism of inhibitory action of PRI-2191 on hydrogen peroxide-evoked toxicity in SH-SY5Y cells. Furthermore, these data point to differential involvement of ERK-MAPK and PI3-K in neuroprotective effects of 1,25 dihydroxyvitamin D(3) and its low-calcemic analogue - PRI-2191.
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PMID:Involvement of PI3-K in neuroprotective effects of the 1,25-dihydroxyvitamin D3 analogue - PRI-2191. 1722 May 48

The mammalian amyloid precursor protein (APP) protein family consists of the APP and the amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2). The neurotoxic amyloid beta-peptide (Abeta) originates from APP, which is the only member of this protein family implicated in Alzheimer disease. However, the three homologous proteins have been proposed to be processed in similar ways and to have essential and overlapping functions. Therefore, it is also important to take into account the effects on the processing and function of the APP-like proteins in the development of therapeutic drugs aimed at decreasing the production of Abeta. Insulin and insulin-like growth factor-1 (IGF-1) have been shown to regulate APP processing and the levels of Abeta in the brain. In the present study, we show that IGF-1 increases alpha-secretase processing of endogenous APP and also increases ectodomain shedding of APLP1 and APLP2 in human SH-SY5Y neuroblastoma cells. We also investigated the role of different IGF-1-induced signaling pathways, using specific inhibitors for phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK). Our results indicate that phosphatidylinositol 3-kinase is involved in ectodomain shedding of APP and APLP1, but not APLP2, and that MAPK is involved only in the ectodomain shedding of APLP1.
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PMID:IGF-1-induced processing of the amyloid precursor protein family is mediated by different signaling pathways. 1730 Oct 53

After the treatment of human neuroblastoma SH-SY5Y cells with retinoic acid for 24 h, the expression of c-Ret receptor tyrosine kinase was greatly elevated. Treatment of SH-SY5Y cells with glial cell line-derived neurotrophic factor under serum-free conditions after incubation of cells with retinoic acid resulted in the phosphorylation of c-Ret receptor tyrosine kinase, with subsequent morphological changes that included formation of neurites and rounding of cell bodies within 24-48 h. The number of neurite-bearing cells decreased with increasing concentrations of mitogen-activated protein kinase-specific and phosphatidylinositol 3-kinase inhibitors. These observations suggest that retinoic acid induces the expression of glial cell line-derived neurotrophic factor-responsive c-Ret receptor tyrosine kinase and that a glial cell line-derived neurotrophic factor-c-Ret receptor tyrosine kinase-induced signal transduction system that might be involved in neurite outgrowth via pathways that include phosphatidylinositol 3-kinase and mitogen-activated protein kinase.
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PMID:Retinoic acid induces functional c-Ret tyrosine kinase in human neuroblastoma. 1743 3

Parkinson's disease is characterized by slow and progressive degeneration of dopaminergic neurons. Increasing evidence has suggested an important role for exposure to pesticides such as rotenone in the pathogenesis of Parkinson's disease. Although rotenone can elicit immune responses in microglia, the intracellular signaling events mediating these effects are poorly defined. Here we show that cell-free supernatants of rotenone-treated monocytic THP-1 cells induced cytotoxicity in dopaminergic neuroblastoma SH-SY5Y cells. Exposure of THP-1 cells to rotenone led to transient production of reactive oxygen species (ROS) and phosphorylation of Akt. Akt activation was also induced by exogenous hydrogen peroxide. Pretreatment of THP-1 cells with either a phosphatidylinositol 3-kinase (PI3K) inhibitor or ROS scavengers prevented Akt activation and protected SH-SY5Y cells from the cytotoxic effect of conditioned media from rotenone-treated THP-1 cells. Rotenone treatment of THP-1 cells also led to upregulation of cyclooxygenase-2 and secretion of prostaglandin E2. These results suggest that rotenone-induced activation of ROS/PI3K/Akt pathway in THP-1 cells leads to the release of factors that are toxic to SH-SY5Y cells and have implications for the onset of Parkinson's disease.
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PMID:Rotenone-induced neurotoxicity of THP-1 cells requires production of reactive oxygen species and activation of phosphatidylinositol 3-kinase. 1748 95

S100 proteins are EF-hand calcium-binding proteins with various intracellular functions including cell proliferation, differentiation, migration, and apoptosis. Some S100 proteins are also secreted and exert extracellular paracrine and autocrine functions. Experimental results suggest that the receptor for advanced glycation end products (RAGE) plays important roles in mediating S100 protein-induced cellular signaling. Here we compared the interaction of two S100 proteins, S100B and S100A6, with RAGE by in vitro assay and in culture of human SH-SY5Y neuroblastoma cells. Our in vitro binding data showed that S100B and S100A6, although structurally very similar, interact with different RAGE extracellular domains. Our cell assay data demonstrated that S100B and S100A6 differentially modulate cell survival. At micromolar concentration, S100B increased cellular proliferation, whereas at the same concentration, S100A6 triggered apoptosis. Although both S100 proteins induced the formation of reactive oxygen species, S100B recruited phosphatidylinositol 3-kinase/AKT and NF-kappaB, whereas S100A6 activated JNK. More importantly, we showed that S100B and S100A6 modulate cell survival in a RAGE-dependent manner; S100B specifically interacted with the RAGE V and C(1) domains and S100A6 specifically interacted with the C(1) and C(2) RAGE domains. Altogether these results highlight the complexity of S100/RAGE cellular signaling.
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PMID:S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. 1772 19

We investigated the mechanism of the neuroprotective properties of chondroitin sulfate (CS), an endogenous perineuronal net glycosaminoglycan, in human neuroblastoma SH-SY5Y cells subjected to oxidative stress. Preincubation with CS for 24 h afforded concentration-dependent protection against H2O2-induced toxicity (50 microM for 24 h) measured as lactic dehydrogenase released to the incubation media; cell death was prevented at the concentrations of 600 and 1000 microM. Cell death caused by a combination of 10 microM rotenone plus 1 microM oligomycin-A (Rot/oligo) was also reduced by CS at concentrations ranging from 0.3 to 100 microM; in this toxicity model, maximum protection was achieved at 3 microM (48%). No significant protection was observed in a cell death model of Ca2+ overload (70 mM K+, for 24 h). H2O2 and Rot/oligo generated reactive oxygen species (ROS) measured as an increase in the fluorescence of dichlorofluorescein diacetate-loaded cells. CS drastically reduced ROS generation induced by both H2O2 (extracellular ROS) and Rot/oligo (intracellular ROS). CS also increased the expression of phosphorylated Akt and heme oxygenase-1 by 2-fold. The protective effects of CS were prevented by chelerythrine, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), cycloheximide, and Sn(IV)-protoporphyrin IX. Taken together, these results show that CS can protect SH-SY5Y cells under oxidative stress conditions by activating protein kinase C, which phosphorylates Akt that, via the phosphatidylinositol 3-kinase/Akt pathway, induces the synthesis of the antioxidant protein heme oxygenase-1.
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PMID:Chondroitin sulfate protects SH-SY5Y cells from oxidative stress by inducing heme oxygenase-1 via phosphatidylinositol 3-kinase/Akt. 1788 94


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