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)

Tumor suppressor genes can be inactivated by various mechanisms, including promoter hypermethylation and loss of heterozygosity. We screened the 10q locus for loss of heterozygosity and the promoter methylation status of PTEN, MGMT, MXI1, and FGFR2 in neuroblastic tumors and neuroblastoma cell lines. Expression of these genes in cell lines was analyzed with reverse transcriptase-polymerase chain reaction. Loss of heterozygosity at 10q was detected in 18% of tumors and microsatellite instability in 14%. Promoter hypermethylation of MGMT appeared in 8% of tumors and 25% of cell lines. Correlation between methylation status and lack of expression was evident for PTEN, FGFR2, and MXI1 and was less clear for MGMT. No associations between these alterations and MYCN amplification, 1p deletion, or aggressive tumor histology could be demonstrated, singly or in combination. These data suggest that 10q alterations might be implicated in the development of a small number of neuroblastomas.
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PMID:Loss of heterozygosity and microsatellite instability on chromosome arm 10q in neuroblastoma. 1735 Apr 60

Gastrin-releasing peptide (GRP), the mammalian equivalent of bombesin (BBS), is an autocrine growth factor for neuroblastoma; its receptor is up-regulated in undifferentiated neuroblastomas. Phosphatidylinositol 3-kinase (PI3K) is a critical cell survival pathway; it is negatively regulated by the PTEN tumor suppressor gene. We have recently found that poorly differentiated neuroblastomas express decreased PTEN protein levels. Moreover, overexpression of the GRP receptor, a member of the G-protein coupled receptor family, down-regulates PTEN expression, resulting in increased neuroblastoma cell growth. Therefore, we sought to determine whether GRP or BBS activates PI3K in neuroblastoma cells (BE(2)-C, LAN-1, SK-N-SH). GRP or BBS treatment rapidly increased phosphorylation of Akt and GSK-3beta in neuroblastoma cells. Inhibition of GRP receptor, with antagonist GRP-H2756 or siRNA, attenuated BBS-induced phosphorylation of Akt. LY294002, a PI3K inhibitor, also abrogated BBS-stimulated phospho-Akt as well as its cell cycle targets. GRP increased G1/S phase progression in SK-N-SH cells. BBS-mediated BrdU incorporation was blocked by LY294002. Our findings identify PI3K as an important signaling pathway for GRP-mediated neuroblastoma cell growth. A novel therapy targeted at GRP/GRP receptor may prove to be an effective treatment option to inhibit PI3K in neuroblastomas.
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PMID:Phosphatidylinositol 3-kinase regulation of gastrin-releasing peptide-induced cell cycle progression in neuroblastoma cells. 1737 15

Neuroblastoma is a frequent pediatric tumor with a poor outcome in spite of aggressive treatment, even with autologous hematopoietic stem cell transplantation. The overall cure rate of 40% is unsatisfactory and new therapeutic strategies are urgently needed. AKT is a major mediator of survival signals that protect cells from apoptosis and regulate cell proliferation. The AKT signaling network is considered a key determinant of the biological aggressiveness of these tumors. In this article, the authors discuss the relation between activators of AKT in neuroblastoma, in particular, growth factors such as IGF-1, TRK, GDNF, VEGF and EGF, and their effects on tumoral proliferation, differentiation and apoptosis. Numerous other proteins interact with AKT in neuroblastoma. Several are relatively well characterized, such as PTEN and retinoic acid; others are new and potentially interesting, such as PKC and anaplastic lymphoma kinase. Specific inhibition of AKT has been studied, such as with LY249002, with significant effects on cell progression and apoptosis in tumoral cells. Moreover, a series of new drugs, such as geldanamycin and rapamycin, directly modify the expression of AKT in tumoral cells. Few specific inhibitors of AKT are available; less specific inhibitors are probably unsuitable therapeutic options in neuroblastoma. Drugs with a direct or indirect inhibitory effect on the AKT pathway, used alone or in combination with other drugs, seem to hold great promise as a new therapeutic modality in neuroblastoma.
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PMID:AKT pathway in neuroblastoma and its therapeutic implication. 1847 Oct 48

Neuroblastoma accounts for nearly 15% of all pediatric cancer-related deaths. We have previously shown that gastrin-releasing peptide (GRP) stimulates neuroblastoma growth, and that its cell surface receptor, GRP-R, is overexpressed in advanced-stage human neuroblastomas; however, the effects of GRP/GRP-R on tumorigenesis and metastasis in vivo are not clearly elucidated. In the present study, we found that GRP-R knockdown in the aggressive cell line BE(2)-C induced cell morphology changes, reduced cell size, decreased cell proliferation, and inhibited DNA synthesis, corresponding to cell cycle arrest at G(2)/M phase. Activated Akt, a crucial regulator of cell survival and metastasis, was down-regulated by GRP-R silencing. In addition, expression of p-p70S6K and its downstream target molecule S6, key regulators of protein synthesis and cell metabolism, were also significantly decreased by GRP-R silencing. GRP-R knockdown also up-regulated the expression of tumor suppressor PTEN, the inhibitor of the PI3K/Akt pathway. Furthermore, silencing GRP-R as well as GRP in BE(2)-C cells suppressed anchorage-independent growth in vitro. Conversely, overexpression of GRP-R in less aggressive SK-N-SH neuroblastoma cells resulted in soft agar colony formation, which was inhibited by a GRP-blocking antibody. Moreover, GRP-R deficiency significantly delayed tumor growth and diminished liver metastases in vivo. Our findings demonstrate that GRP and GRP-R have important oncogenic properties beyond their established mitogenic functions. Therefore, GRP-R may be an ideal therapeutic target for the treatment of aggressive neuroblastomas.
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PMID:Gastrin-releasing peptide receptor silencing suppresses the tumorigenesis and metastatic potential of neuroblastoma. 1875 28

CpG island hypermethylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation. In this study, we performed methylation-specific PCR (MSP) to investigate the methylation status of 10 selected tumor suppressor genes in neuroblastoma. Seven of the investigated genes (CD44, RASSF1A, CASP8, PTEN, ZMYND10, CDH1, PRDM2) showed high frequencies (> or =30%) of methylation in 33 neuroblastoma cell lines. In 42 primary neuroblastoma tumors, the frequencies of methylation were 69%, CD44; 71%, RASSF1A; 56%, CASP8; 25%, PTEN; 15%, ZMYND10; 8%, CDH1; and 0%, PRDM2. Furthermore, CASP8 and CDH1 hypermethylation was significantly associated with poor event-free survival. Meta-analysis of 115 neuroblastoma tumors demonstrated a significant correlation between CASP8 methylation and MYCN amplification. In addition, there was a correlation between ZMYND10 methylation and MYCN amplification. The MSP data, together with optimized mRNA re-expression experiments (in terms of concentration and time of treatment and use of proper reference genes) further strengthen the notion that epigenetic alterations could play a significant role in NB oncogenesis. This study thus warrants the need for a global profiling of gene promoter hypermethylation to identify genome-wide aberrantly methylated genes in order to further understand neuroblastoma pathogenesis and to identify prognostic methylation markers.
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PMID:Aberrant methylation of candidate tumor suppressor genes in neuroblastoma. 1881 46

Neuroblastomas, which mostly occur in children, are aggressive metastatic tumors of the sympathetic nervous system. The failure of the previous therapeutic regimens to target multiple components of N-Myc pathway resulted in poor prognosis. The present study investigated the efficacy of the combination of N-(4-hydroxyphenyl) retinamide (4-HPR, 0.5 microM) and genistein (GST, 25 microM) to control the growth of human neuroblastoma cells (SH-SY5Y and SK-N-BE2) harboring divergent molecular attributes. Combination of 4-HPR and GST down regulated N-Myc, Notch-1, and Id2 to induce neuronal differentiation. Transition to neuronal phenotype was accompanied by increase in expression of e-cadherin. Induction of neuronal differentiation was associated with decreased expression of hTERT, PCNA, survivin, and fibronectin. This is the first report that combination of 4-HPR and GST mediated reactivation of multiple tumor suppressors (p53, p21, Rb, and PTEN) for early cell cycle exit (due to G1/S phase arrest) in neuroblastoma cells. Reactivation of tumor suppressor(s) repressed N-Myc driven growth factor mediated angiogenic and invasive pathways (VEGF, b-FGF, MMP-2, and MMP-9) in neuroblastoma. Repression of angiogenic factors led to the blockade of components of mitogenic pathways [phospho-Akt (Thr 308), p65 NF-kappaB, and p42/44 Erk 1/2]. Taken together, the combination of 4-HPR and GST effectively blocked survival, mitogenic, and angiogenic pathways and activated proteases for apoptosis in neuroblastoma cells. These results suggested that combination of 4-HPR and GST could be effective for controlling the growth of heterogeneous human neuroblastoma cell populations.
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PMID:N-Myc down regulation induced differentiation, early cell cycle exit, and apoptosis in human malignant neuroblastoma cells having wild type or mutant p53. 1954 Feb 7

Parkinson's disease (PD) is a devastating neurodegenerative disease characterized by a distinct set of motor symptoms. Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) or parkin have been linked to early-onset autosomal recessive forms of familial PD. We have recently shown that parkin (an E3 ubiquitin ligase) and PINK1 (a serine/threonine kinase) affect one other's stability, solubility, and tendency to form cytoprotective aggresomes (Um et al., 2009). Here we validated the functional relevance of this mutual interaction under pathologic PD conditions, by investigating the changes of expression and solubility of these factors in response to PD-linked toxins. Consistent with our previous cell culture data, exposure of human dopaminergic neuroblastoma SH-SY5Y cells to PD-linked toxins (1-methyl-4-phenylpyridinium ion, 6-hydroxydopamine, or MG132) reduced Nonidet P-40-soluble parkin levels and induced PINK1 accumulation. Consistent with our previous findings from parkin knockout mice, rat models of PD (6-hydroxydopamine-, rotenone-, or MG132-induced PD) were also associated with an increase in soluble and insoluble PINK1 levels as well as enhanced formation of parkin aggregates. These findings suggest that both PINK1 and parkin play important roles in regulating the formation of Lewy bodies during the pathogenesis of sporadic and familial PD.
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PMID:Formation of parkin aggregates and enhanced PINK1 accumulation during the pathogenesis of Parkinson's disease. 2017 Nov 92

PI3K/AKT/mTOR pathway signalling is often upregulated in cancer, usually by the constitutional activation of growth factor receptors, amplification or mutation of PIK3CA and loss of tumour suppressor PTEN function. The way of PI3K/AKT/mTOR pathway activation in neuroblastoma (NB) is not well established. The study was performed on paraffin-embedded tissue sections from 106 patients with NB. The aim of the study was to analyse the mutational status of EGFR (exons 18-21), PIK3CA (exons 5, 6, 10 and 21) and PTEN (all exons) genes, as well as to assess expression of their protein products by immunohistochemistry. A novel mutation in exon 5 of PIK3CA, c.931 A>G (p.I311V), in two infantile tumours (2.7%) was identified. In addition some polymorphisms were found in all examined genes, including a novel one, c.285 A>T in PTEN. Polymorphism PIK3CA c.1060-17 C>A was significantly more frequent in extra-adrenal tumours. Polymorphism PIK3CA c.1145+54 A>G showed a tendency to be more frequent in children older than 18 months and in extra-adrenal tumours. Expression of EGFR was present in 95% of cases, PI3Kp110 in 92% of tumours and PTEN in all tumours (low in 39%) and did not correlate with the genetic alterations. EGFR and PTEN expression showed an association with tumour differentiation. Mutations in the EGFR, PIK3CA and PTEN genes are infrequent in neuroblastoma. Both newly detected mutations in exon 5 of PIK3CA occurred in very low risk neuroblastic tumours in infants. EGFR, PI3Kp110 and PTEN expression is a common feature of NB.
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PMID:EGFR, PIK3CA and PTEN gene status and their protein product expression in neuroblastic tumours. 2122 6

Neuroblastoma (NB) represents one of the most common paediatric tumours. Despite advance in NB research and treatment, the outcome of the patients from the high-risk group remains poor. PI3K/AKT/mTOR signalling pathway which is involved in oncogenesis and cancer progression of many tumours, in parallel constitutes the target for the biologically based oncological therapy. In this study we analyzed the status of PI3K/AKT/mTOR signalling route in the primary tumour tissue samples from a group of 39 high-risk NB. The pathway activation state was assessed immunohistochemically using antibodies with specificity towards PI3Kp85, PI3Kp110, phospho-AKT, phospho-mTOR, phospho-p70S6K and phospho-4EBP1. Moreover, expression of PTEN, bcl2 and cyclin D1 was examined. We found that most of tumours were positive for PI3Kp85 and PI3Kp110, as well as for p-AKT, p-mTOR and its downstream effectors p-p70S6K and p-4EBPI. PTEN was expressed in all cases, bcl2 and cyclin D1 staining was found in more than 90% of examined NB. Statistical analysis revealed that p-AKT expression was correlated with p-mTOR and strong cyclin D1 labelling. Furthermore, high expression of p-4EBP1 was significantly associated with p-p70S6K expression, high cyclin D1 and lower differentiation of the tumour. PI3K/AKT/mTOR signalling pathway activation is a common event in high-risk NB and it seems that this group of patients may benefit from targeted therapy with kinase inhibitors.
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PMID:Analysis of PI3K/AKT/mTOR signalling pathway in high risk neuroblastic tumours. 2129 Mar 41

Mutations in PTEN-induced kinase 1 (PINK1) are associated with a familial syndrome related to Parkinson's disease (PD). We previously reported that stable neuroblastoma SH-SY5Y cell lines with reduced expression of endogenous PINK1 exhibit mitochondrial fragmentation, increased mitochondria-derived superoxide, induction of compensatory macroautophagy/mitophagy and a low level of ongoing cell death. In this study, we investigated the ability of protein kinase A (PKA) to confer protection in this model, focusing on its subcellular targeting. Either: (1) treatment with pharmacological PKA activators; (2) transient expression of a constitutively active form of mitochondria-targeted PKA; or (3) transient expression of wild-type A kinase anchoring protein 1 (AKAP1), a scaffold that targets endogenous PKA to mitochondria, reversed each of the phenotypes attributed to loss of PINK1 in SH-SY5Y cells, and rescued parameters of mitochondrial respiratory dysfunction. Mitochondrial and lysosomal changes in primary cortical neurons derived from PINK1 knockout mice or subjected to PINK1 RNAi were also reversed by the activation of PKA. PKA phosphorylates the rat dynamin-related protein 1 isoform 1 (Drp1) at serine 656 (homologous to human serine 637), inhibiting its pro-fission function. Mimicking phosphorylation of Drp1 recapitulated many of the protective effects of AKAP1/PKA. These data indicate that redirecting endogenous PKA to mitochondria can compensate for deficiencies in PINK1 function, highlighting the importance of compartmentalized signaling networks in mitochondrial quality control.
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PMID:Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease. 2163 91


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