Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PURPOSE:Gastrin-releasing peptide (GRP) is a 27-amino acid neuropeptide that has been identified in the cytoplasm of many neuroendocrine tumors. Gastrin releasing peptide has been labeled as an autocrine growth factor in small cell lung carcinomas. Recent work has also shown this to be true in the growth of neuroblastoma cells in vitro. The purpose of this study was to demonstrate GRP and its receptor (GRP-R) in resected human neuroblastomas and to correlate the presence or absence with other known predictors of poor prognosis.To demonstrate the presence of GRP and GRP-R mRNA, total RNA was extracted from human neuroblastoma cells. A reverse transcription-polymerase chain reaction (RT-PCR) was then performed using specific primers. The products of the RT-PCR were then confirmed to be GRP and GRP-R cDNA by Southern blot analysis. The RT-PCR products were then sequenced, and these sequences were compared with the know sequences of GRP and GRP-R DNA.N = 19. GRP and GRP-R mRNA were present in all neuroblastoma specimens. Although no correlation with other known predictors of poor prognosis existed, transcripts of four different sizes (400, 450, 500, and 950 bp) were seen in the GRP-R transcripts. The sequences of the 950 bp-sized transcript reverse transcription PCR products were identical to the known GRP-R.We conclude that gastrin releasing peptide and gastrin releasing peptide receptor mRNA are present in all human neuroblastomas. Although qualitatively it appears to lack prognostic significance, its ubiquitous nature in the tumor suggests it may be a useful target on which to base future treatment modalities.
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PMID:Gastrin-releasing peptide: a potential growth factor expressed in human neuroblastoma tumors(1). 1122 44

As a neuroendocrine tumor, neuroblastoma expresses various gastrointestinal (GI) hormones, such as vasoactive intestinal peptide, gastrin-releasing peptide (GRP), neurotensin, and somatostatin, which exert diverse cellular functions in neuroblastoma. In particular, we have recently found that GRP and its cell surface receptor, GRP-R, are abundantly expressed in neuroblastomas. Moreover, more advanced-stage neuroblastomas demonstrated an increased level of GRP-R, suggesting an important role of GRP in aggressive tumor behavior. This review describes the role of several GI hormones commonly expressed in neuroblastoma and discusses in depth the mitogenic actions of GRP in neuroblastoma. In addition, the molecular mechanisms involved in the GRP-induced stimulation of neuroblastoma cell growth are discussed. Our study results demonstrate a role of GRP as an autocrine/paracrine growth factor and elucidate involvement of specific intracellular signaling, the phosphatidylinositol 3-kinase pathway, in the growth regulation of neuroblastoma.
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PMID:Role of gastrointestinal hormones in neuroblastoma. 1570 38

Gastrin-releasing peptide (GRP) activates phosphatidylinositol 3-kinase (PI3-K)/Akt, an important cell survival signaling pathway, to stimulate growth of various cell types. Transforming growth factor (TGF) superfamily ligands activate intracellular Smad signaling to regulate cell growth, differentiation and apoptosis; dysregulation of the TGF-beta/Smad pathway has been noted in cancer cells. Therefore, we sought to determine whether a potential cross-talk exists between the TGF-beta/Smad and PI3-K pathways in the regulation of neuroblastoma cell growth. Increased Smad DNA binding was noted in SK-N-SH human neuroblastoma cells when treated with LY294002, an inhibitor of PI3-K, by transcription factor/DNA array analysis and electrophoretic mobility shift assay. LY294002 treatment resulted in Smad2 accumulation in the nuclei and an increased Smad binding element (SBE)-luciferase activity. These findings were corroborated by co-transfection with pCGNN-Deltap85 plasmid, which expresses a PI3-K mutant p85 subunit. In contrast, GRP treatment decreased Smad binding activity in neuroblastoma cells. Our findings demonstrate that the PI3-K pathway negatively regulates TGF-beta/Smad signaling in neuroblastoma cells. GRP-induced activation of PI3-K, resulting in neuroblastoma cell growth promotion, is potentiated by down-regulation of TGF-beta/Smad signaling.
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PMID:Inhibition of transforming growth factor-beta/Smad signaling by phosphatidylinositol 3-kinase pathway. 1641 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

Gastrin-releasing peptide (GRP), the mammalian equivalent of bombesin (BBS), is a trophic factor for highly vascular neuroblastomas; its mechanisms of action in vivo are unknown. We sought to determine the effects of BBS on the growth of neuroblastoma xenografts and on angiogenesis. BBS significantly increased the growth of SK-N-SH and BE(2)-C human neuroblastomas; tumors demonstrated increased expression of angiogenic markers, PECAM-1 and VEGF, as well as phosphorylated (p)-Akt levels. RC-3095, a BBS/GRP antagonist, attenuated BBS-stimulated tumor growth and angiogenesis in vivo. GRP or GRPR silencing significantly inhibited VEGF as well as p-Akt and p-mTOR expression in vitro. Our findings demonstrate that BBS stimulates neuroblastoma growth and the expression of angiogenic markers. Importantly, these findings suggest that novel therapeutic agents, targeting BBS-mediated angiogenesis, may be useful adjuncts in patients with advanced-stage neuroblastomas.
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PMID:Bombesin induces angiogenesis and neuroblastoma growth. 1738 15

Angiogenesis plays a critical role in tumor progression in various cancers, including neuroblastoma. We have previously shown that gastrin-releasing peptide (GRP) stimulates neuroblastoma growth and that its cell surface receptors, gastrin-releasing peptide receptors (GRP-R), are overexpressed in advanced-stage human neuroblastomas; however, the effects of GRP on angiogenesis are not clearly elucidated. Interleukin (IL) 8, a proinflammatory chemokine, plays an important role during tumor angiogenesis. Ets transcription factors, such as oncoproteins, cause tumor development and are also known to induce IL-8 expression. In the present study, we found an increased expression of Ets1 in more undifferentiated human neuroblastomas. Stable transfection of SK-N-SH human neuroblastoma cells with Ets1 plasmid resulted in increased IL-8 luciferase activity and IL-8 secretion into cell culture media. Conversely, silencing of Ets1 resulted in a significant decrease in IL-8 secretion in SK-N-SH cells. Moreover, exogenous GRP treatment increased Ets1 (T38) phosphorylation and Ets1 nuclear accumulation, and enhanced Ets1 binding to its DNA consensus sequence, resulting in the stimulation of IL-8 mRNA expression and protein secretion. Our findings demonstrate that GRP upregulates proangiogenic IL-8 expression in an Ets1-dependent manner, suggesting a critical role of this process during GRP-induced neuroblastoma angiogenesis and metastasis.
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PMID:Ets1 transcription factor mediates gastrin-releasing peptide-induced IL-8 regulation in neuroblastoma cells. 1740 58

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

Gastrin-releasing peptide (GRP) acts as an autocrine growth factor for neuroblastoma and other types of cancer, and its cell-surface receptor, GRPR, is overexpressed in advanced-stage human neuroblastoma. GRPR knockdown and GRPR antagonism inhibit the growth of experimental neuroblastoma. Here we show that a GRPR antagonist promotes rather than inhibits the growth of neuroblastoma cells. The GRPR antagonist, RC-3095, at 0.1 nM inhibited, whereas at 100 nM stimulated proliferation of Neuro2a murine neuroblastoma cells in vitro. The stimulatory effects were prevented by the histone deacetylase inhibitor (HDACi), sodium butyrate (NaB). Expression of GRPR mRNA in Neuro2a cells was analyzed by RT-PCR. These findings provide evidence that a GRPR antagonist can stimulate the growth of cancer cells, and suggest that GRPR might interact with epigenetic mechanisms in regulating neuroblastoma cell growth.
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PMID:A gastrin-releasing peptide receptor antagonist stimulates Neuro2a neuroblastoma cell growth: prevention by a histone deacetylase inhibitor. 1942 21

Increasing evidence indicates that the neuronal gastrin-releasing peptide-preferring bombesin receptor (GRPR) is a key molecular regulator of fear memory formation. However, the downstream signaling events remain poorly understood. The protooncogene product phosphoinositide 3-kinase (PI3K) has been implicated in regulating memory formation, as well as in mediating cellular responses to GRPR activation in glioma and neuroblastoma cells. We show here that GRPR modulation of fear memory consolidation in the rat hippocampus requires PI3K activation. Male Wistar rats received bilateral infusions of the GRPR agonist bombesin (BB) or the PI3K inhibitor LY294002 into the CA1 region of the dorsal hippocampus immediately after inhibitory avoidance (IA) conditioning. BB enhanced, whereas LY294002 impaired, IA memory retention. The BB-induced memory enhancement was blocked by coinfusion of either a GRPR antagonist or LY294002. These findings provide the first evidence suggesting that PI3K signaling is required for GRPR regulation of CNS function.
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PMID:Phosphoinositide 3-kinase is required for bombesin-induced enhancement of fear memory consolidation in the hippocampus. 1946 55

Activation of PI3K/AKT pathway correlates with poor prognosis in patients with neuroblastoma. Our previous studies have demonstrated that PI3K/AKT signaling is critical for the oncogenic transformations induced by gastrin-releasing peptide (GRP) and its receptor, GRP-R, in neuroblastoma. Moreover, PI3K/AKT-dependent oncogenic transformations require N-myc, an extensively studied oncogene in neuroblastoma. Whether AKT directly regulates the expression of N-myc oncogene is yet to be determined. Here, we report a novel finding that of the three AKT isoforms, AKT2 specifically regulated N-myc expression in neuroblastoma cells. We also confirmed that GRP-R is upstream of AKT2 and in turn, regulated N-myc expression via AKT2 in neuroblastoma cells. Functional assays demonstrated that attenuation of AKT2 impaired cell proliferation and anchorage-independent cell growth, and decreased the secretion of angiogenic factor VEGF in vitro. Furthermore, silencing AKT2 inhibited migration and invasion of neuroblastoma cells in vitro. Xenografts established by injecting AKT2 silenced human neuroblastoma cells into murine spleen expressed decreased levels of AKT2 and resulted in fewer liver metastases compared to controls in vivo. Hence, our study highlights the potential molecular mechanism(s) mediating the oncogenic role of GRP/GRP-R and demonstrates a novel role for AKT2 in neuroblastoma tumorigenesis, indicating that targeting the GRP/GRP-R/AKT2 axis may be important for developing novel therapeutics in the treatment of clinically aggressive neuroblastoma.
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PMID:Akt2 regulates metastatic potential in neuroblastoma. 2346 63


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