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)

Induction of cyclooxygenase-2 (COX-2) in the brain of people infected with human immunodeficiency virus type 1 (HIV-1) has been proposed as a cause of cognitive impairment in AIDS dementia. Here, we have analyzed the molecular mechanism by which its induction takes place in neuroblastoma cells. The HIV-1 envelope protein gp120 was able to induce COX-2 mRNA and protein in several human neuroblastoma cell lines, which express CXCR4 and CCR5 but not CD4. Moreover, gp120 induces COX-2 promoter transcription. Sequential deletions of the promoter show that deletion of a distal nuclear factor-kappaB (NF-kappaB) site abrogated gp120-dependent transcription. More importantly, overexpression of NF-kappaB inhibitory subunit, IkappaBalpha, completely abrogated gp120-induced COX-2 activity. However, transfection of p65/relA NF-kappaB was not enough to induce COX-2 transcription, suggesting that NF-kappaB was necessary but not sufficient to control COX-2 transcription induced by gp120. In addition to NF-kappaB, activating protein-1 (AP-1) but not nuclear factor of activated T cells (NFAT)-dependent transcription was induced by gp120. Transfection of a dominant negative mutant c-Jun protein, TAM-67, efficiently blocked the induction of COX-2 promoter by gp120, confirming AP-1 requirement. Moreover, gp120 rapidly activates the c-Jun amino-terminal kinase (JNK) and p38 mitogen-activated protein kinase phosphorylation. The importance of NF-kappaB and AP-1 in COX-2 promoter and protein induction was corroborated by using pharmacological NF-kappaB, p38 and JNK inhibitors.
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PMID:Human immunodeficiency virus type 1 envelope glycoprotein 120 induces cyclooxygenase-2 expression in neuroblastoma cells through a nuclear factor-kappaB and activating protein-1 mediated mechanism. 1600 69

CXCR4, a chemokine receptor constitutively expressed in the brain, binds both ligands, the chemokine SDF-1alpha and the HIV envelope glycoprotein gp120(IIIB). There seem to be intracellular differences between the neuronal apoptosis induced by SDF-1alpha and that induced by gp120(IIIB), but the apoptotic pathways involved have not been compared in human neuronal cells. In this study, we characterized the apoptotic intracellular pathways activated by neurotoxic concentrations of SDF-1alpha and gp120(IIIB) in human neuroblastoma cells SK-N-SH. SDF-1alpha (10 nM) and gp120(IIIB) (2 nM) induced similar levels of apoptosis after 24 h of incubation (49 +/- 4% and 48 +/- 3%, respectively, of the neurons were apoptotic). SDF1alpha-induced apoptosis was completely abolished by the inhibition of Src phosphorylation by PP2. Exposure to SDF-1alpha (10 nM) triggered an increase in Src phosphorylation, with a maximum after 20 min of incubation (1.80 +/- 0.24 times higher than control, P = 0.01). NMDA calcium flux was enhanced only if cells were incubated with SDF-1alpha for 20 min before applying NMDA. By contrast, gp120(IIIB)-induced apoptosis was not affected by the inhibition of Src phosphorylation. Moreover, gp120(IIIB) enhanced NMDA calcium flux immediately, without modifying Src phosphorylation status. Finally, levels of phospho-JNK increased following exposure to gp120(IIIB) (by a factor of 1.46 +/- 0.4 at 120 min, P = 0.03), but not after exposure to SDF-1alpha. Thus, SDF-1alpha and gp120(IIIB) induced a similar level of neuronal apoptosis, but by activating different intracellular pathways. SDF-1alpha enhanced NMDA activity indirectly via Src phosphorylation, whereas gp120(IIIB) probably activated the NMDA receptor directly and phosphorylated JNK.
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PMID:Effects of SDF-1alpha and gp120IIIB on apoptotic pathways in SK-N-SH neuroblastoma cells. 1648 Nov 5

The chemokine receptor CXCR4 functions as human immunodeficiency virus (HIV)-1 coreceptor and is involved in acquired immunodeficiency virus (AIDS) neuropathogenesis. CXCR4 is expressed by most cell types in the brain, including microglia, astrocytes, and neurons. Studies have shown that the HIV envelope protein gp120 binds to neuronal CXCR4 and activates signal transduction pathways leading to apoptosis. However, the natural CXCR4 ligand (CXCL12) has been referred to induce both neuronal survival and death. Here the authors used flow cytometry to determine whether gp120 and CXCL12 differ in their ability to induce CXCR4 internalization in the human neuroblastoma cells SH-SY5Y, which constitutively express CXCR4. As expected, increasing concentration of CXCL12 reduced surface expression of CXCR4 in a time-and concentration-dependent manner. Conversely, gp120IIIB (monomeric or oligomeric, in presence or absence of soluble CD4) did not change CXCR4 membrane levels. Similar results were obtained in a murine lymphocyte cell line (300-19) stably expressing human CXCR4. Nevertheless, gp120IIIB was still able to activate intracellular signaling and proapoptotic pathways, via CXCR4. These results show that gp120IIIB toxicity and signaling do not require CXCR4 internalization in SH-SY5Y cells, and suggest that the viral protein may alter normal CXCR4 trafficking thus, interfering with activation of prosurvival pathways.
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PMID:Human immunodeficiency virus gp120-induced apoptosis of human neuroblastoma cells in the absence of CXCR4 internalization. 1687 2

Despite HAART, a significant number of HIV-1-infected patients develop neurological complications. However, the presence of specific neurotropic HIV-1 strains, the extent of viral replication in the brain, and the type of cells infected remain controversial issues. To address this controversy we have analyzed different V3 loop sequences of viral isolates from four vertically HIV-1-infected children who developed HIV-1-related encephalopathy. Moreover, we have determined that some biological and molecular properties of HIV-1 might contribute to AIDS neurological dysfunctions. We detected very different HIV-1 isolates (X4 and R5) in the brain despite no great differences in clinical, pathological, or immunological parameters. In vitro, no differences in replicative competence in glial or neuroblastoma cells were observed between virus isolated from the blood of children with or without clinical neurological symptoms. The expression of both CXCR4 and CCR5 RNAs was observed in the brain independently of HIV-1 infection and viral strain predominant in this location. Our results failed to show a particular phenotypic property of the HIV-1 virus that might explain its neurovirulence and/or neurotropism.
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PMID:Lack of association of HIV-1 biological or molecular properties with neurotropism for brain cells. 1695 3

Neuroblastoma (NB) is derived from intrinsic migratory neural crest cells and has a high potential for distant metastasis. Growing evidence has implicated chemokine receptors, especially CXCR4, which normally control immune and inflammatory cell migration, as having important roles in tumor progression. In this study, we investigated the expression of CXCR4 in eight different NB cell lines and found that CXCR4 expression is dynamically regulated in NB and can be modulated by different tissue stromata. In addition, we demonstrate that IL-5 and IFN-gamma are released from stromal cells and act as differential mediators for CXCR4 expression. We also overexpressed CXCR4 in two NB cell lines, NUB-7 and SK-N-BE(2), and studied the role of CXCR4 in NB metastasis both in vitro and in vivo. In vitro transwell invasion assay showed that CXCR4 overexpression promoted NB cell migration preferentially toward a bone marrow stromal cell-conditioned medium. Using an in vivo xenograft model, CXCR4-overexpressing cells showed an increased incidence of metastasis, most notably bone marrow metastasis. Our studies reveal critical roles for CXCR4 in NB metastasis and provide insights into the regulatory mechanism of chemokine receptors in NB and the importance of the tissue microenvironment in modulating tumor cell behavior.
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PMID:Tissue microenvironment modulates CXCR4 expression and tumor metastasis in neuroblastoma. 1732 42

The activity of Topoisomerase II alpha and beta isoforms is tightly regulated during different phases of cell cycle. In the present study, the action of anti-inflammatory agents, nordihydroguaretic acid (NDGA) is analyzed in HIV-1 infected CXCR4(+), CCR5(+) and CD4(-) SK-N-SH neuroblastoma, CXCR4(+), CCR5(+) and CD4(-) 1321N1 astrocytoma and CXCR4(+), CCR5(+/-) and CD4(-) GO-G-CCM glioblastoma cell lines. In SK-N-SH and 1321N1 the expression of Topoisomerase II alpha is concomitant with that of LOX-5 and is highly sensitive to NDGA, while the Topoisomerase II beta is expressed along with TNFalpha and exhibits low sensitivity to NDGA, suggesting distinct pathways of regulation for the two isoforms. HIV-1 infection in these cells enhanced the expression of Topo II alpha and beta. Further, the regulation of Topo II beta and TNFalpha in infected and uninfected SK cells is distinctly different. HIV-1 gp120 derived peptides could block HIV-1 mediated inflammation and Topoisomerase II alpha and beta expression, suggesting the viral mediated response. A combination of NDGA, gp-120 derived peptides and AZT has completely blocked the viral replication, suggesting the enhancement of potency of AZT under the suppression of inflammatory response. In contrast, the expression of Topo II alpha and beta was stimulated by NDGA in GO-G-CCM cells showing distinct regulatory pathway in these cells that was resistant to HIV-1 infection. This suggests the requirement of inflammatory response for productive viral infection. In summary, an induction of co-receptor mediated inflammatory response can distinctly enhance regulated expression of the cellular Topo II alpha and beta and promote productive infection in neurons and astrocytes.
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PMID:Regulation of topoisomerase II alpha and beta in HIV-1 infected and uninfected neuroblastoma and astrocytoma cells: involvement of distinct nordihydroguaretic acid sensitive inflammatory pathways. 1739 42

Neuroblastoma (NB) is a heterogeneous, and particularly malignant childhood neoplasm in its higher stages, with a propensity to form metastasis in selected organs, in particular liver and bone marrow, and for which there is still no efficient treatment available beyond surgery. Recent evidence indicates that the CXCR4/CXCL12 chemokine/receptor axis may be involved in promoting NB invasion and metastasis. In this study, we explored the potential role of CXCR4 in the malignant behaviour of NB, using a combination of in vitro functional analyses and in vivo growth and metastasis assessment in an orthotopic NB mouse model. We show here that CXCR4 overexpression in non-metastatic CXCR4-negative NB cells IGR-NB8 and in moderately metastatic, CXCR4 expressing NB cells IGR-N91, strongly increased tumour growth of primary tumours and liver metastases, without altering the frequency or the pattern of metastasis. Moreover shRNA-mediated knock-down experiments confirmed our observations by showing that silencing CXCR4 in NB cells impairs in vitro and almost abrogates in vivo growth. High levels of CXCL12 were detected in the mouse adrenal gland (the primary tumour site), and in the liver suggesting a paracrine effect of host-derived CXCL12 on NB growth. In conclusion, this study reveals a yet unreported NB-specific predominant growth and survival-promoting role of CXCR4, which warrants a critical reconsideration of the role of CXCR4 in the malignant behaviour of NB and other cancers.
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PMID:The chemokine receptor CXCR4 strongly promotes neuroblastoma primary tumour and metastatic growth, but not invasion. 1792 64

Many cancer cells display down-regulated major histocompatibility complex (MHC) class I antigen (MHC-I), which seems to enable them to evade immune surveillance, whereas the underlying mechanisms remain incompletely understood. Here, we demonstrate that ligand (CXCL12) stimulation of CXCR4, a major chemokine receptor expressed in many malignant cancer cells, induced MHC-I heavy chain down-regulation from the cell surface of the human epithelioid carcinoma HeLa cells, the human U251 and U87 glioblastoma cells, the human MDA-MD 231 breast cancer cells, and the human SK-N-BE (2) neuroblastoma cells. Activation of CXCR4 also induced MHC-I down-regulation in human peripheral blood mononuclear cells. The internalized MHC-I heavy chain molecules were partially co-localized with Rab7, a later endosomal marker. Activation of CXCR4 induced ubiquitination of MHC-I heavy chain, and mutation of the C-terminal two lysine residues (Lys-332, Lys-337) on one of the MHC-I alleles, HLA.B7, blocked CXCR4-evoked ubiquitination and down-regulation of HLA.B7. Moreover, purified GST-conjugated CXCR4 C terminus directly associated with the purified His-tagged beta2-microglobulin (beta2M), and MHC-I heavy chain was co-immunoprecipitated with CXCR4 in a beta2M-dependent manner. This interaction appears to be critical for CXCR4-evoked down-regulation of MHC-I heavy chain as evidenced by the data that MHC-I heavy chain down-regulation was inhibited by either truncation of the CXCR4 C terminus or knockdown of beta2M. All together, these findings shed new light on the role of CXCR4 in tumor evasion of immune surveillance via inducing MHC-I down-regulation from the cell surface.
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PMID:Activation of CXCR4 triggers ubiquitination and down-regulation of major histocompatibility complex class I (MHC-I) on epithelioid carcinoma HeLa cells. 1808 6

Neuroblastoma is the second most common pediatric malignancy. The clinical course of this disease ranges from spontaneous regression and good survival to highly malignant therapy-resistant tumors. There is a continuous need for genetic and biologic markers for the diverse clinical phenotypes observed in neuroblastoma patients. One of the known markers in neuroblastoma is expression of the CXCR4 chemokine receptor. CXCR4 expression correlates with high-stage disease, and the autocrine stimulation of CXCR4 by its ligand (CXCL12) was shown to be necessary for the survival of some neuroblastoma cells in vitro. However, the mechanisms responsible for activation of the CXCL12-CXCR4 autocrine pathway in neuroblastoma remain uncertain. Our previous findings suggest that Csk homologous kinase (CHK) is a physiological inhibitor of CXCR4 expression. Since CHK is highly expressed in neurons, we evaluated changes in CHK expression in human neuroblastoma. CHK protein expression was below detectable levels based on Western blot analyses in 13 out of 16 human neuroblastoma cell lines and in 6 out of 16 primary neuroblastoma tissues. When CHK expression was restored in IMR32 neuroblastoma cells by retrovirus-mediated cDNA transfer, diminished CXCR4 mRNA and protein levels were observed, as assessed by RT-PCR and flow cytometry analyses, respectively. Furthermore, exogenous expression of CHK markedly suppressed the mRNA levels and secretion of the CXCL12 chemokine from IMR32 cells as well as inhibited the growth rate of these cells. Taken together, our data strongly suggest that CHK is capable of inhibiting the CXCL12-CXCR4 pathway in neuroblastoma.
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PMID:Csk homologous kinase inhibits CXCL12-CXCR4 signaling in neuroblastoma. 1829 39

Chemokine receptors, and in particular CXCR4 and CCR5 play a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV)4 associated dementia (HAD). Thus, new insight into the expression of CXCR4 in the central nervous system may help develop therapeutic compounds against HAD. Brain-derived neurotrophic factor (BDNF) is neuroprotective in vitro against two strains of the HIV envelope protein gp120 that binds to CXCR4 or CCR5. Therefore, we examined whether BDNF modulates chemokine receptor expression in vivo. The content of CXCR4 mRNA and proteins was determined in the cerebral cortex and hippocampus of 6-month-old BDNF heterozygous mice and wild type littermates by using polymerase chain reaction and immunohistochemistry, respectively. BDNF heterozygous mice exhibited an increase in CXCR4 mRNA compared to wild type. Histological analyses revealed an up-regulation of CXCR4 immunoreactivity mainly in neurons. Most of these neurons were positive for TrkB, the BDNF receptor with a tyrosine kinase activity. Increases in CXCR4 mRNA levels were observed in 18-month-old BDNF heterozygous mice but not in 7-day-old mice, suggesting that the modulatory role of BDNF occurs only in mature animals. To determine whether BDNF affects also CXCR4 internalization, SH-SY5Y neuroblastoma cells were exposed to BDNF and cell surface CXCR4 levels were measured at various times. BDNF induced CXCR4 internalization within minutes. Lastly, BDNF heterozygous mice showed higher levels of CCR5 and CXCR3 mRNA than wild type in the cerebral cortex, hippocampus and striatum. Our data indicate that BDNF may modulate the availability of chemokine receptors implicated in HIV infection.
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PMID:Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain. 1858 60


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