Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using the in situ liver model system, we have recently shown that, after cholera toxin binding to hepatic cells, cholera toxin accumulates in a low-density endosomal compartment, and then undergoes endosomal proteolysis by the aspartic acid protease cathepsin-D [Merlen C, Fayol-Messaoudi D, Fabrega S, El Hage T, Servin A, Authier F (2005) FEBS J272, 4385-4397]. Here, we have used a subcellular fractionation approach to address the in vivo compartmentalization and cytotoxic action of cholera toxin in rat liver parenchyma. Following administration of a saturating dose of cholera toxin to rats, rapid endocytosis of both cholera toxin subunits was observed, coincident with massive internalization of both the 45 kDa and 47 kDa Gsalpha proteins. These events coincided with the endosomal recruitment of ADP-ribosylation factor proteins, especially ADP-ribosylation factor-6, with a time course identical to that of toxin and the A subunit of the stimulatory G protein (Gsalpha) translocation. After an initial lag phase of 30 min, these constituents were linked to NAD-dependent ADP-ribosylation of endogenous Gsalpha, with maximum accumulation observed at 30-60 min postinjection. Assessment of the subsequent postendosomal fate of internalized Gsalpha revealed sustained endolysosomal transfer of the two Gsalpha isoforms. Concomitantly, cholera toxin increased in vivo endosome acidification rates driven by the ATP-dependent H(+)-ATPase pump and in vitro vacuolar acidification in hepatoma HepG2 cells. The vacuolar H(+)-ATPase inhibitor bafilomycin and the cathepsin D inhibitor pepstatin A partially inhibited, both in vivo and in vitro, the cAMP response to cholera toxin. This cathepsin D-dependent action of cholera toxin under the control of endosomal acidity was confirmed using cellular systems in which modification of the expression levels of cathepsin D, either by transfection of the cathepsin D gene or small interfering RNA, was followed by parallel changes in the cytotoxic response to cholera toxin. Thus, in hepatic cells, a unique endocytic pathway was revealed following cholera toxin administration, with regulation specificity most probably occurring at the locus of the endosome and implicating endosomal proteases, such as cathepsin D, as well as organelle acidification.
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PMID:Role of receptor-mediated endocytosis, endosomal acidification and cathepsin D in cholera toxin cytotoxicity. 1745 37

Xanthohumol is the major prenylated flavonoid present in the hop plant Humulus lupulus L. (Cannabinaceae) and a common ingredient of beer. Recently, xanthohumol has gained considerable interest due to its potential cancer chemo-preventive effect. The aim of this study was to reveal the possible anti-genotoxic activity of xanthohumol in metabolically competent human hepatoma HepG2 cells, by use of the comet assay. Xanthohumol by itself was neither cytotoxic nor genotoxic to the cells at concentrations below 10microM. However, a significant protective effect against the pro-carcinogens benzo(a)pyrene (BaP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was observed at concentrations as low as 0.01microM. In cells treated with xanthohumol in combination with tert-butyl hydroperoxide (t-BOOH) - an inducer of reactive oxygen species (ROS) - no protective effect was observed and xanthohumol also showed no significant scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. On the other hand, HepG2 cells pre-treated with xanthohumol showed significantly reduced levels of t-BOOH-induced DNA strand breaks, indicating that its protective effect is mediated by induction of cellular defence mechanisms against oxidative stress. As xanthohumol is known to be an effective inhibitor of cytochrome P450 enzymes and an inducer of NAD(P)H: quinone reductase (QR), our findings can be explained by an inhibition of metabolic activation of pro-carcinogens and/or by induction of carcinogen-detoxifying and anti-oxidative enzymes by xanthohumol. These results provide evidence that xanthohumol displays anti-genotoxic activity in metabolically competent human cells.
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PMID:Protective effects of xanthohumol against the genotoxicity of benzo(a)pyrene (BaP), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and tert-butyl hydroperoxide (t-BOOH) in HepG2 human hepatoma cells. 1759 Mar 82

Chronic ethanol feeding causes liver steatosis in animal models by upregulating the sterol regulatory element-binding protein 1 (SREBP-1), which subsequently increases the synthesis of hepatic lipid. SREBP-1 activity is regulated by reversible acetylation at specific lysine residues. The present study tests the hypothesis that activation of SREBP-1 by ethanol may be mediated by mammalian sirtuin 1 (SIRT1), a NAD(+)-dependent class III protein deacetylase. The effects of ethanol on SIRT1 were determined in cultured rat hepatoma cells and in the livers of ethanol-fed mice. In rat H4IIEC3 cells, we observed that ethanol exposure induced SREBP-1c lysine acetylation and SREBP-1c transcriptional activity. The effect of ethanol was abolished by expression of wild-type SIRT1 or by treatment with resveratrol, a known potent SIRT1 agonist. Conversely, knocking down SIRT1 by the small silencing SIRT1 plasmid SIRT1shRNA or expression of a SIRT1 mutant, SIRT1(H363Y), did not negate the ethanol effect. These findings suggest that the effect of ethanol on SREBP-1 is mediated, at least in part, through SIRT1 inhibition. Consistent with the in vitro findings, chronic ethanol feeding substantially downregulated hepatic SIRT1 in mice. Inhibition of hepatic SIRT1 activity was associated with an increase in the acetylated active nuclear form of SREBP-1c in the livers of ethanol-fed mice. Our results indicate an essential role for SIRT1 in mediating the effects of ethanol on SREBP-1 and hepatic lipid metabolism, as well as the development of alcoholic fatty liver. Hence, SIRT1 may represent a novel therapeutic target for treatment of human alcoholic fatty liver disease.
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PMID:Involvement of mammalian sirtuin 1 in the action of ethanol in the liver. 1823 56

Benzo[a]pyrene (BaP), a member of polycyclic aromatic hydrocarbons (PAH), has been reported to induce cell death in various cell types. However, the underlying mechanisms are controversial. In the present study, we report that BaP induces necrotic cell death in human hepatoma (HepG(2)) cells. The process is dependent on the activation of poly(ADP-ribose)polymerase-1 (PARP-1), a nuclear enzyme responsible for repairing DNA damage. Once activated, PARP-1 catalyzes the formation of ADP-ribose polymers on acceptor proteins at the expense of NAD(+). Incubation of cells with high extracellular concentration of NAD(+) (5mM) after BaP treatment caused an elevation in intracellular NAD(+) level and blocked cell death. Inhibitor of PARP-1 suppressed both overactivation of PARP-1 activity and NAD(+) depletion. Moreover, addition of pyruvate (5mM), but not glutamate (5mM) or glutamine (5mM), could restore ATP production and prevent cell death. These results elucidated a sequence of events linking cellular metabolism to the progression of cell death induced by this organic toxicant.
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PMID:Benzo[a]pyrene-induced necrosis in the HepG(2) cells via PARP-1 activation and NAD(+) depletion. 1824 66

Although the spatial and temporal distributions of cellular NAD(P)H concentrations have been theoretically predicted as typical patterns of the metabolism in living cells, so far such a pattern was observed only in neutrophils. In this work, the dynamic NAD(P)H distributions in rat basophilic leukemia (RBL-2H3) and human hepatocellular carcinoma (Hep G2) cells were studied by imaging the autofluorescence of cellular NAD(P)H with a sensitive CCD detector in a confocal microscope. The typical pattern of the cytoplasmic NAD(P)H wave traveling along the long axis of the elongated cell with a velocity of 2.2+/-0.6 mircom/s was detected in RBL-2H3 cells. While in the case of Hep G2 cells, only the oscillation of the mitochondrial NAD(P)H was observed because the NAD(P)H mainly localized in mitochondria of Hep G2 cells. These results confirm the metabolic pattern of NAD(P)H in living cells and suggest that the expression of the metabolic pattern probably differs in different cell lines.
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PMID:Metabolic patterns (NAD(P)H) in rat basophilic leukemia (RBL-2H3) cells and human hepatocellular carcinoma (Hep G2) cells with autofluorescence imaging. 1895 92

Posttranslational modifications play a key role in recruiting chromatin remodeling and modifying enzymes to specific regions of chromosomes to modulate chromatin structure. Alc1 (amplified in liver cancer 1), a member of the SNF2 ATPase superfamily with a carboxy-terminal macrodomain, is encoded by an oncogene implicated in the pathogenesis of hepatocellular carcinoma. Here we show that Alc1 interacts transiently with chromatin-associated proteins, including histones and the poly(ADP-ribose) polymerase Parp1. Alc1 ATPase and chromatin remodeling activities are strongly activated by Parp1 and its substrate NAD and require an intact macrodomain capable of binding poly(ADP-ribose). Alc1 is rapidly recruited to nucleosomes in vitro and to chromatin in cells when Parp1 catalyzes PAR synthesis. We propose that poly(ADP-ribosyl)ation of chromatin-associated Parp1 serves as a mechanism for targeting a SNF2 family remodeler to chromatin.
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PMID:Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. 1966 85

NAD(P)H: quinone oxidoreductase 1 (NQO1), a cytosolic enzyme which catalyzes the two-electron reduction of quinone compounds, has been suggested to prevent the generation of semiquinone free radicals and reactive oxygen species, thus protecting cells from oxidative damage. However, the enzymatic activity of NQO1 strongly depends on the individual genetic polymorphism of the NQO1 gene. A common NQO1 polymorphism is a C to T transition at position 609, which results in an inactive enzyme. Recent studies showed that NQO1 is an important enzyme for stabilizing p53 protein, which is involved in anti-tumorigenesis. Thus, the lack of enzymatic activity in the homozygous C609T NQO1 polymorphism may play a pivotal role in tumor development. This study aimed to investigate the relationship between C609T NQO1 polymorphism and p53 expression in human hepatocellular carcinoma (HCC). Genotyping of NQO1 was performed on 100 HCC specimens by PCR-RFLP analysis. In addition, NQO1 and p53 protein expression in HCC samples at different TNM stages was determined by immunohistochemistry. Our data showed that (1) the frequency of C609T NQO1 was significantly increased in TNM stage III HCC patients; (2) no significant association was found between p53 expression and C609T polymorphism of NQO1 gene; and (3) a tumor/non-tumor (T/N) ratio > 1.27 of NQO1 expression revealed by real-time qPCR analyses was positively correlated with poorer survival in patients with tumors >5 cm, suggesting that an increase of NQO1 expression may be an indicator of advanced tumor progression. This study provides important information about NQO1 genotypes and its expression to HCC tumor development and progression.
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PMID:Analysis of NQO1 polymorphisms and p53 protein expression in patients with hepatocellular carcinoma. 1968 91

To identify metabolic pathways involved in hepatic lipoapoptosis, metabolic flux analysis using [U-(13)C(5)]glutamine as an isotopic tracer was applied to quantify phenotypic changes in H4IIEC3 hepatoma cells treated with either palmitate alone (PA-cells) or both palmitate and oleate in combination (PA/OA-cells). Our results indicate that palmitate inhibited glycolysis and lactate dehydrogenase fluxes while activating citric acid cycle (CAC) flux and glutamine uptake. This decoupling of glycolysis and CAC fluxes occurred during the period following palmitate exposure but preceding the onset of apoptosis. Oleate co-treatment restored most fluxes to their control levels, resulting in steatotic lipid accumulation while preventing apoptosis. In addition, palmitate strongly increased the cytosolic NAD(+)/NADH ratio, whereas oleate co-treatment had the opposite effect on cellular redox. We next examined the influence of amino acids on these free fatty acid-induced phenotypic changes. Increased medium amino acids enhanced reactive oxygen species (ROS) generation and apoptosis in PA-cells but not in PA/OA-cells. Overloading the medium with non-essential amino acids induced apoptosis, but essential amino acid overloading partially ameliorated apoptosis. Glutamate was the most effective single amino acid in promoting ROS. Amino acid overloading also increased cellular palmitoyl-ceramide; however, ceramide synthesis inhibitors had no effect on measurable indicators of apoptosis. Our results indicate that free fatty acid-induced ROS generation and apoptosis are accompanied by the decoupling of glycolysis and CAC fluxes leading to abnormal cytosolic redox states. Amino acids play a modulatory role in these processes via a mechanism that does not involve ceramide accumulation.
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PMID:Effect of anaplerotic fluxes and amino acid availability on hepatic lipoapoptosis. 1975 88

Our preliminary experiment demonstrated that a n-hexane/EtOH (9:1, volume) extract of Glycyrrhiza uralensis (licorice) caused a significant induction of NAD(P)H:oxidoquinone reductase (NQO1), one of the well-known phase 2 detoxifying enzymes. We isolated dehydroglyasperin C (DGC) as a potent phase 2 enzyme inducer from licorice. DGC induced NQO1 both in wild-type murine hepatoma Hepa1c1c7 and ARNT-lacking BPRc1 cells, indicating that the compound is a monofunctional inducer. The compound induced not only NQO1 but also some other phase 2 detoxifying/antioxidant enzymes, such as glutathione S-transferase, gamma-glutamylcysteine synthase, glutathione reductase, and heme oxygenase 1. Similar to most monofunctional inducers, DGC caused the accumulation of Nrf2 in the nucleus in dose- and time-dependent manners and thereby activated expression of phase 2 detoxifying enzymes. It also resulted in a dose-dependent increase in the luciferase activity in the reporter assay, in which HepG2-C8 cells transfected with antioxidant response element (ARE)-luciferase construct were used, suggesting that the induction of phase 2 detoxifying and antioxidant enzymes could be achieved through the interaction of Nrf2 with the ARE sequence in the promoter region of their genes.
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PMID:Dehydroglyasperin C isolated from licorice caused Nrf2-mediated induction of detoxifying enzymes. 2008 9

Recent studies demonstrated the carcinogenicity and the mutagenicity of vanadium compounds. In addition, vanadium (V(5+)) was found to enhance the effects of other genotoxic agents. However, the mechanism by which V(5+) induce toxicity remain unknown. In the current study we examined the effect of V(5+) (as ammonium metavanadate, NH(4)VO(3)) on the expression of NAD(P)H: quinone oxidoreductase 1 (NQO1) in human hepatoma HepG2 cells. Therefore, HepG2 cells were treated with increasing concentrations of V(5+) in the presence of two NQO1 inducers, the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and isothiocyanate sulforaphane (SUL). Our results showed that V(5+) inhibited the TCDD- and SUL-mediated induction of NQO1 at mRNA, protein and activity levels. Investigating the effect of V(5+) at transcriptional levels revealed that V(5+) significantly inhibited the TCDD- and SUL-mediated induction of antioxidant responsive element (ARE)-dependent luciferase reporter gene expression. In addition, V(5+) was able to decrease the TCDD- and SUL-induced nuclear accumulation of nuclear factor erythroid 2-related factor-2 (Nrf2) without affecting Nrf2 mRNA or protein levels. Looking at the post-transcriptional level, V(5+) did not affect NQO1 mRNA stability, thus eliminating the possible role of V(5+) in decreasing NQO1 mRNA levels through this mechanism. In contrast, at post-translational level, V(5+) was able to significantly decrease NQO1 protein half-life. The present study demonstrates for the first time that V(5+) down-regulates NQO1 at the transcriptional and post-translational levels in the human hepatoma HepG2 cells via AhR- and Nrf2-dependent mechanisms.
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PMID:Modulation of NAD(P)H:quinone oxidoreductase by vanadium in human hepatoma HepG2 cells. 2059 94


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