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)

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that has been shown to play a major role in adipocyte and monocyte/macrophage differentiation. Recent work has also suggested a role for PPARgamma in cell cycle control and/or differentiation of other cell types including breast and lung cancer cells. Using reverse transcription-PCR, we now show for the first time that human neuroblastoma (nb) cells express PPARbeta and -gamma, but not -alpha. Using the LA-N-5 nb cell line, we have determined that the natural PPARgamma ligand 15-deoxy-delta prostaglandin J2, as well as the synthetic PPARgamma agonist GW1929, can stimulate the differentiation of nb cells, as evidenced by the inhibition of cell proliferation, neurite outgrowth, increased acetylcholinesterase activity, and the reduction of N-myc expression. We have also demonstrated that PPARgamma is expressed in primary nb and, furthermore, that the expression of this receptor correlates with the maturational stage of the nb cells. Taken together, these studies have implicated a role for PPARgamma in peripheral nerve cell biology and suggest that the PPARgamma signaling pathway is involved in the regulation of nb cell growth and differentiation.
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PMID:Novel expression and function of peroxisome proliferator-activated receptor gamma (PPARgamma) in human neuroblastoma cells. 1120 25

Although considerable research has shown a role for peroxisome proliferator-activated receptors (PPAR) in adipose differentiation and in the regulation of inflammation, little is known about its possible functions in neurons. We investigated the role of PPARgamma in primary cultures of cortical neurons and human neuroblastoma SH-SYSY cells. Incubation of cortical neurons with the specific PPARgamma ligand 15-Deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) induced morphological changes including neurite degeneration and nuclear condensation that were consistent with neurons dying by apoptosis. The morphological changes associated with incubation of cortical neurons with 15d-PGJ2 were prevented following pretreatment of neurons with the general caspase inhibitor, Z-VAD. These results highlight a novel role for PPARgamma in neurons and suggest that unwarranted activation of PPARgamma may contribute to the neuronal apoptosis associated with certain neurodegenerative disorders including Alzheimer's disease (AD).
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PMID:15-deoxy-delta12,14-prostaglandin J2, a specific ligand for peroxisome proliferator-activated receptor-gamma, induces neuronal apoptosis. 1127 93

Phenylacetate (PA) is a member of a class of aromatic fatty acids that has demonstrated antitumor activity in experimental models and in humans. Previous reports have shown that PA and its analogues can act as ligands for the peroxisome proliferator-activated receptor (PPAR) and thereby regulate certain gene expression through peroxisome proliferator response elements. The role of this activity in the antitumor activity of PA has not been determined. To address this question, we have used the human neuroblastoma cell line LA-N-5, which expresses PPARgamma and can be induced to differentiate with PA and with classical PPARgamma ligands. Our results indicated that the PPARgamma ligands 15-deoxy- prostaglandin J2 and GW1929 as well as PA induced LA-N-5 cells to differentiate to a similar phenotype as evidenced by inhibition of cell proliferation, neurite outgrowth, increased acetylcholinesterase activity, and decreased N-myc gene expression. Furthermore, induction with all of the compounds was accompanied by up-regulation of mRNA levels of the nuclear retinoic acid receptor beta (RARbeta) and specific activation of a reporter gene construct (SVbetaRE-CAT) that contains the canonical RA response element located in the RARbeta promoter. All of the assessed functional and molecular effects of PA on LA-N-5 cells, as well as those of the classical PPARgamma ligands, were inhibited by cotreatment with specific PPARgamma antagonists (GW9662 and/or GW0072). Taken together, these studies have confirmed a role for PPARgamma in neuroblastoma cell biology and indicated that the PPARgamma signaling pathway plays a direct role in the PA-induced differentiation response of this cell type.
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PMID:Differentiation of human neuroblastoma by phenylacetate is mediated by peroxisome proliferator-activated receptor gamma. 1135 17

Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a superfamily of thyroid / steroid hormone receptors and regulates transcription of their target genes in a ligand-dependent manner. Recently, PPARgamma was reported to be expressed in several cell lines derived from breast, colon, stomach and lung cancers. Activation of PPARgamma by its ligand inhibits the growth of these tumor cells, suggesting that PPARgamma ligand is a potential anti-cancer agent in PPARgamma-expressing tumors. However, its expression in brain tumors has not been studied. We thus studied the expression in glioma samples with different pathological stages from 20 patients. It was demonstrated that 95% of the glioma tissue expressed PPARgamma mRNA. The results prompted us to study whether PPARgamma ligand affects the growth of cell lines derived from brain tumors. The receptor expression was studied in 9 cell lines either derived from malignant glioma or neuroblastoma. The expression was detected in a glioma cell line SK-MG-1 and in a neuroblastoma cell line NB-1. Addition of one of the PPARgamma ligands, troglitazone, induced growth inhibition in both cell lines. Further analyses revealed that this growth inhibition is caused by a PPARgamma-mediated induction of apoptosis. These results suggest that PPARgamma ligands could be a potential therapeutic agent for the treatment of the brain tumors expressing this receptor.
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PMID:Expression of PPARgamma and its ligand-dependent growth inhibition in human brain tumor cell lines. 1207 14

Peroxisome proliferator-activated receptors (PPARs) are involved in regulating many metabolic and inflammatory processes. The present study explores the role of PPAR ligands in protecting neuronal cultures from toxic insults. For that purpose, we used WY14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid] as a PPARalpha agonist, L-165041 and L-783483 as PPARbeta ligands, and 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2), troglitazone, and ciglitazone for PPARgamma. Experiments were performed using HT-22, an immortalized mouse hippocampal cell line, and SK-N-SH, a human neuroblastoma cell line. Cell viability against glutamate, hydrogen peroxide (H(2)O(2)), and serum deprivation insults was determined using a calcein acetoxymethyl (AM) assay. Of the compounds tested, only 15d-PGJ2 and troglitazone showed a dose-dependent neuroprotection from glutamate and H(2)O(2) insults in HT-22 cells. None of the PPAR agonists was protective in SK-N-SH cells. A minimum of 4-6 h preincubation with 15d-PGJ2 was required to achieve significant neuroprotection. On the other hand, troglitazone was protective even when administered simultaneously with glutamate, or for up to 8 h postglutamate insult. To investigate whether the neuroprotective effects are mediated through PPARgamma, we first determined through Western blotting that HT-22 and SK-N-SH cells express PPARgamma. However, the neuroprotective effects of those compounds are unlikely to be mediated through the PPARgamma for two reasons: (1) various concentrations of another PPARgamma agonist (ciglitazone) were not neuroprotective; (2) by itself, PPAR exhibits a low affinity for DNA, and high-affinity binding requires heterodimerization with RXR, the 9-cis-retinoic acid receptor; administering 9-cis-retinoic acid in conjunction with 15d-PGJ2 did not alter the neuroprotective effects of the latter. Our results demonstrate neuroprotective effects of 15d-PGJ2 and troglitazone that are likely independent of PPARgamma.
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PMID:Neuroprotective effects of PPARgamma agonists against oxidative insults in HT-22 cells. 1286 Apr 74

PPARgamma (peroxisome proliferator-activated receptor gamma) is a ligand-activated transcription factor that responds to 15dPGJ2 (15-deoxy-Delta12,14-prostglandin J2). 15dPGJ2, in vitro, halts neuroblastoma cell growth, but reported mechanisms vary. Here we evaluated the modulatory effects of endogenous serum lipid mitogens upon the extent of 15dPGJ2-induced growth inhibition and on the precise cellular responses of neuroblastoma cells to PPARgamma activation. We show that 15dPGJ2 specifically inhibited cell growth in both complete and delipidated media. 15dPGJ2-induced growth inhibition was accompanied by decreased cell viability, although the effect was far more marked in delipidated medium than in complete medium. Incubation with 15dPGJ2 in complete medium resulted in cytoplasmic changes characteristic of type II programmed cell death (autophagy), while prior serum lipid removal resulted in cell death via an apoptotic mechanism. These distinct, serum lipid-dependent cellular responses to 15dPGJ2 were accompanied by increases in the expression of a reporter gene construct containing a PPAR response element of 2.3-fold in complete medium, but of 4.8-fold in delipidated medium. Restoration of the serum lysolipid LPA (lysophosphatidic acid) to cells in delipidated medium reduced 15dPGJ2-mediated PPARgamma activation, growth inhibition and cell death; following addition of S1P (sphingosine 1-phosphate), decreases were apparent but more marginal. Further, while the effects of LPA in delipidated medium were mediated through a G(i)/phosphoinositide 3-kinase/MAPK (mitogen-activated protein kinase) pathway, those of S1P did not involve the MAPK component. These data suggest that the serum lysolipid LPA modulates the degree of PPARgamma activation and the precise cellular response to 15dPGJ2 via activation of a G(i)/phosphoinositide 3-kinase/MAPK pathway.
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PMID:Lysophosphatidic acid attenuates the cytotoxic effects and degree of peroxisome proliferator-activated receptor gamma activation induced by 15-deoxyDelta12,14-prostaglandin J2 in neuroblastoma cells. 1517 82

Neuroblastoma (NB) is a phenotypically heterogeneous tumor, displaying cells of neuronal, melanocytic, or glial/schwannian lineage. This cellular heterogeneity is also present in vitro, where cells of neuroblastic (N)- or stromal (S)-type may be identified. Ligands of peroxisome proliferator-activated receptor gamma (PPARgamma) have been shown to inhibit growth in different tumor cell lines. The purpose of this study was to determine PPARgamma expression and the response to its ligands in NB cell lines with different phenotypes. We used eight NB cell lines with N-, mixed, and S-phenotype. PPARgamma expression was found in all NB cell lines, regardless of their phenotype. Mutational analysis and transactivation assays showed that PPARgamma is not mutated and remains functional in NB cells. Two PPARgamma ligands, 15-deoxy-delta12,14-prostaglandin J2 (PGJ2) and rosiglitazone, inhibited growth of all cell lines, with PGJ, being the most potent agent. PGJ2, but not rosiglitazone, induced arrest of the cells in the G2/M phase as well as apoptosis. The sensitivity to the two ligands appeared to be more related to the phenotype than PPARgamma expression, with the S-type cells being less sensitive than the N-type, partly because of their lower capability of undergoing apoptosis. No synergistic effect on growth inhibition was observed when all cell lines were co-treated with 9-cis retinoic acid (9-cis RA) and rosiglitazone. Our data indicate that PPARgamma expression and function are maintained in phenotipically different NB cell lines. Activation of PPARgamma by its synthetic ligands might have a therapeutic role in advanced NB.
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PMID:The cellular response to PPARgamma ligands is related to the phenotype of neuroblastoma cell lines. 1530 25

Neuroblastoma is a childhood cancer, which spontaneously regresses. This has led to a search for agents that mimic this process. We show that both natural and synthetic ligands of PPARgamma (peroxisome-proliferator-activated receptor gamma) inhibit the growth of neuroblastoma cells in vitro. The degree of PPAR activation was attenuated however in the presence of the retinoblastoma protein. Addition of trichostatin A, a histone deacetylase inhibitor, abolished retinoblastoma protein repression of PPAR activity. Moreover, enhanced growth inhibition was observed when neuroblastoma cells were treated with a PPARgamma ligand and a histone deacetylase inhibitor, suggesting a combination therapy to treat neuroblastoma might prove more effective than using either agent alone.
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PMID:Regulation of cellular processes by PPARgamma ligands in neuroblastoma cells is modulated by the level of retinoblastoma protein expression. 1549 29

Induction of apoptosis by the death ligand TRAIL might be a promising therapeutic approach in cancer therapy. However, since not all tumor cells are sensitive to TRAIL, there is a need for the development of strategies to overcome TRAIL-resistance. The results of the present study show that the anti-diabetic drug troglitazone sensitizes human glioma and neuroblastoma cells to TRAIL-induced apoptosis. This process is accompanied by a substantial increase of active caspase 8 and active caspase 3, but it is independent of troglitazone's effects on the nuclear receptor PPAR-gamma. Troglitazone induces a pronounced reduction in protein expression levels of the anti-apoptotic FLICE-inhibitory protein (FLIP) without affecting FLIP mRNA levels. Further, protein and mRNA expression levels of the anti-apoptotic protein Survivin significantly decrease upon treatment with troglitazone. Moreover, sensitization to TRAIL is partly accompanied by an up-regulation of the TRAIL receptor, TRAIL-R2. A combined treatment with troglitazone and TRAIL might be a promising experimental therapy because troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via various mechanisms, thereby minimizing the risk of acquired tumor cell resistance.
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PMID:Troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via down-regulation of FLIP and Survivin. 1682 Sep 65

Neuroblastoma (NB) is the most common extracranial solid tumour in infants. Unfortunately, most children present with advanced disease and have a poor prognosis. In the present study, we evaluated the role of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone (RGZ) in two NB cell lines (SK-N-AS and SH-SY5Y), which express PPARgamma. Rosiglitazone decreased cell proliferation and viability to a greater extent in SK-N-AS than in SH-SY5Y. Furthermore, 20 microM RGZ significantly inhibited cell adhesion, invasiveness and apoptosis in SK-N-AS, but not in SH-SY5Y. Because of the different response of SK-N-AS and SH-SY5Y cells to RGZ, the function of PPARgamma as a transcriptional activator was assessed. Noticeably, transient transcription experiments with a PPARgamma responsive element showed that RGZ induced a three-fold increase of the reporter activity in SK-N-AS, whereas no effect was observed in SH-SY5Y. The different PPARgamma activity may be likely due to the markedly lower amount of phopshorylated (i.e. inactive) protein observed in SK-N-AS. To our knowledge, this is the first demonstration that the differential response of NB cells to RGZ may be related to differences in PPARgamma transactivation. This finding indicates that PPARgamma activity may be useful to select those patients, for whom PPARgamma agonists may have a beneficial therapeutic effect.
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PMID:Antineoplastic effects of rosiglitazone and PPARgamma transactivation in neuroblastoma cells. 1696 47


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