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

The effect of hydrogen peroxide (H2O2) on the expression of different antioxidant enzymes was investigated in primary rat hepatocytes and the rat hepatoma H4IIE cell line. Catalase mRNA expression and enzyme activity decreased during rat hepatocyte culture. Exposure of hepatocytes to H2O2 prevented this decrease in catalase mRNA expression, catalase expression was induced 2-fold. MnSOD message levels showed a peak after 12 h of culture and MnSOD enzyme activity increased similarly. MnSOD mRNA expression was also induced after exposure to H2O2. Cu/ZnSOD mRNA expression remained constant during culturing and was not affected by H2O2 treatment. In confluent hepatoma H4IIE cells catalase mRNA expression was lower than in early hepatocyte cultures and could be induced 2-fold upon treatment with H2O2. Actinomycin D alone caused the same amount of induction of catalase mRNA in rat hepatocytes as in combination with H2O2. Exposure of hepatocytes to cycloheximide did not influence the induction of catalase mRNA by H2O2. In rat hepatoma H4IIE cells the induction of catalase mRNA by H2O2 was prevented by the addition of actinomycin D or cycloheximide. Although induction of catalase mRNA by H2O2 was found in rat hepatocytes and H4IIE cells, gene expression of catalase does not appear to be regulated in both cell types in the same manner.
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PMID:Alterations of antioxidant enzyme expression in response to hydrogen peroxide. 943 11

In present study we studied the cytotoxic effects of beta-lapachone, a potent anticancer drug, on the human hepatoma cell line (HepA2) under serum-free condition. Most cells died after 2 microM beta-lapachone addition at 48 hours. No apoptotic characteristics of DNA ladder was documented by agarose DNA electrophoresis. The blockage of cell cycle at S phase and unscheduled DNA synthesis were demonstrated by flow cytometric analysis and anti-bromodeoxyuridine immunocytochemistry. Ultrastructural observation showed that the swollen mitochondria, dilatation and vesiculation of rER and proliferation of peroxisome-like granules appeared within the cytoplasm of HepA2 cells following drug treatment. Using enzyme cytochemistry, both peroxidase and acid phosphatase activities but not catalase activity were localised in these peroxisome-like granules. Therefore, these results suggested that (a) beta-lapachone has a novel cytotoxic effect on human hepatoma cell; (2) beta-lapachone induces the interruption of the cell cycle and unscheduled DNA synthesis in HepA2 cells; and (3) beta-lapachone promotes the proliferation of peroxisome-like granules containing peroxidase and acid phosphatase activities without evidence of catalase activity in hepatoma cell line.
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PMID:beta-Lapachone induced cell death in human hepatoma (HepA2) cells. 947 38

This review summarizes our comparative study of the antitumor action of sodium 5,6-benzylidene-L-ascorbate (SBA) and sodium ascorbate. Both SBA and ascorbate produced ascorbate radicals during decomposition, elevated oxidation potential and oxidized methionine to methionine sulfoxide, in the regular culture medium. They induced apoptotic cell death (characterized by internucleosomal DNA fragmentation) in human myelogenous leukemic cell lines, but killed most of other tumor cell lines by necrosis without induction of internucleosomal DNA fragmentation. The cytotoxic activity of SBA and ascorbate was significantly enhanced in the presence of copper and the stimulation effect of copper was reduced by a heavy metal antagonist. However, the cytotoxic activity of SBA was only slightly modified by iron, cysteine analog or catalase, in contrast to ascorbate, which was highly sensitive to all these agents. Furthermore, intravenous administration of SBA induced degeneration in chemically-induced hepatocellular carcinoma whereas ascorbate was inactive. These data suggest the differential mode of antitumor action between these two compounds.
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PMID:Comparative study of the antitumor action between sodium 5,6-benzylidene-L-ascorbate and sodium ascorbate (minireview). 949 48

Chronic griseofulvin (GF) feeding induces preneoplastic foci followed by hepatocellular carcinoma in the mouse liver. Our previous study suggested that GF-induced hepatocellular proliferation had a different mechanism from that of peroxisome proliferator (PP)-induced direct hyperplasia. The GF-induced hepatocellular proliferation was mediated through activation of immediate early genes such as Fos, Jun, Myc, and NFKB. In contrast, PP-induced direct hyperplasia does not involve activation of any of these immediate early genes. It has been shown that nuclear hormone receptors including peroxisome proliferator activated receptors (PPARs) and retinoid x receptors (RXRs) play important roles in mediating the pleiotropic effects of PPs. To examine the possible roles of PPARs and RXRs during non-PP-induced hepatocellular proliferation and the interaction between PP and non-PP-induced proliferation, we have studied the expression of the PPAR and RXR genes in the GF model using northern blot hybridizations and gel retardation assays. The data showed that the expression of PPARalpha and RXRalpha genes was down-regulated in the livers containing preneoplastic nodules and in the liver tumors induced by GF. The mRNA down-regulation was accompanied by a decrease in the amount of nuclear protein-bound to peroxisome proliferator and retinoic acid responsive elements. Down-regulation was also associated with the suppressed expression of the PPARalpha/RXRalpha target genes (i.e., acyl-Co oxidase and cytochrome P450 4A1) and the catalase gene. The RXR-gamma gene was also down-regulated, but the RARalpha, beta, and gamma and PPARbeta and gamma genes were up-regulated. These results indicated that the hepatocarcinogenesis induced by GF is accompanied by suppression of the PPARalpha/RXRalpha-mediated direct hyperplasia pathway. The differential expression of these nuclear hormone receptors reveals a new aspect for understanding the individual roles and intercommunication of PPAR, RXR, and RAR isoforms in the liver.
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PMID:Inhibition of PPAR alpha/RXR alpha-mediated direct hyperplasia pathways during griseofulvin-induced hepatocarcinogenesis. 954 66

Oxidative stress interferes with several cellular functions, in particular transcriptional regulation. We show here that the human cytochrome P450 1A1 (CYP1A1) is down-regulated at the transcriptional level by oxidative stress. Basal as well as 2,3,7, 8-tetrachloro-p-dioxin-induced promoter activities are strongly impaired by H2O2 treatment or glutathione depletion with L-buthionine-(S,R)-sulfoximine. Tumor necrosis factor alpha inhibits CYP1A1 expression, and this inhibition is prevented by the antioxidant pyrrolidine dithiocarbamate. We show that these regulations depend on the integrity of the nuclear factor 1 (NFI) site located in the proximal promoter. We therefore examined the redox regulation of this transcription factor. Treatment of human HepG2 or rat H4 hepatoma cells with H2O2 or L-buthionine-(S, R)-sulfoximine inactivates the binding of the NFI transcription factor to its DNA consensus sequence. Furthermore, H2O2 treatment leads to a dose-dependent decrease of reporter gene expressions driven by promoters containing NFI binding sites. Glutathione depletion and catalase inhibition also repress a NFI-driven promoter. Under the same conditions, the CP-1 transcription factor activity is not affected by oxidative stress. Thus, NFI seems particularly sensitive to oxidative stress. This accounts, at least partially, for the regulation of cyp1A1 gene expression.
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PMID:Down-regulation of cytochrome P450 1A1 gene promoter by oxidative stress. Critical contribution of nuclear factor 1. 975 46

Erythropoietin (Epo) synthesis is suppressed in normoxia and stimulated in hypoxia. To test the hypothesis that the cellular H2O2 level is important in the control of Epo synthesis, we have studied effects of modulators of H2O2 generation and degradation on Epo production in human hepatic cell cultures (hepatoma lines HepG2 and Hep3B). In addition, we measured the activities of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) in cultures following hypoxia exposure or H2O2 treatment. The results show that the formation of immunoreactive Epo was stimulated in normoxic cultures by treatment with exogenous catalase thus mimicking the effect of hypoxia (24 h incubation periods). Epo production was also stimulated when scavengers of reactive O2 species (tetramethylthiourea, dihydrorhodamine) were added to the cells. On the other hand, stimulators of H2O2 generation (xanthine oxidase, glucose oxidase, NADH, NADPH) lowered Epo production in hypoxic cultures. Hypoxia exposure decreased superoxide dismutase activity and H2O2 treatment reduced catalase activity thus influencing the endogenous antioxidant defense system. These findings support the concept that reactive O2 species, primarily H2O2, act as messengers in the O2-dependent control of the hepatic production of Epo. Changes in the cellular activities of antioxidant enzymes appear to play only a minor role in this process.
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PMID:Effects of modulators of the production and degradation of hydrogen peroxide on erythropoietin synthesis. 986 91

We investigated whether the antitumor action of sodium 5,6-benzylidene-L-ascorbate (SBA) is mediated via oxidation-involved mechanism, in three different systems: 3'-methyl-4-dimethylaminoazobenzene (DAB)-induced rat hepatocellular carcinoma (in vivo), its homogenate (semi in vivo), and cultured cells (in vitro). Oral intake of DAB irreversibly produced hepatocellular carcinoma in rats, with a maximum incidence of carcinogenesis after 4 months. Intravenous administration of SBA induced vacuolar, eosinophilic degeneration and nuclear debris, producing greater amounts of ESR signal of ascorbate radical and hydrogen peroxide (H2O2)-derived chemiluminescence (CL) (H2O2-CL) in the cancerous tissue than in the normal tissue. When SBA was directly added to the homogenates, higher amounts of ascorbate radical and H2O2-CL were generated in cancerous tissues. When SBA was added to the RPMI1640 medium supplemented with 10% fetal bovine serum, methionine was oxidized to methionine sulfoxide and H2O2 was produced in amounts that sufficiently induce apoptotic cell death in human promyelocytic leukemic HL-60 cells. Cytotoxic activity of SBA was significantly reduced by catalase. These data suggest that antitumor activity of SBA in vivo might at least in part be due to H2O2, produced from SBA.
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PMID:Production of hydrogen peroxide in cancerous tissue by intravenous administration of sodium 5,6-benzylidene-L-ascorbate. 1022 47

The mechanisms involved in the anti-carcinogenic activity of selenium remain to be elucidated. In the present study, we examined sodium selenite-induced oxidative stress and apoptosis in a human hepatoma cell line (HepG2). Sodium selenite (10 microM) exerted clear cytotoxic effect, as shown by the significant increase of lactate dehydrogenase leakage. Selenite-induced DNA alterations in apoptosis were studied by: 1. comet assay; 2. TdT-mediated dUTP nick end-labeling assay. In addition, characteristic apoptotic morphological alterations were also observed in selenite-treated cells. Our results clearly show that Se-induced cell death occurs predominantly in the form of apoptosis. Selenite-induced oxidative stress was evaluated by the measurement of reactive oxygen species production using lucigenin-dependent chemiluminescence. The involvement of glutathione in selenite-induced oxidative stress was further demonstrated by the concurrent decline of intracellular reduced glutathione and increase of oxidized glutathione contents in Se-treated cells. Moreover, the finding that selenite-induced oxidative stress and apoptosis was significantly attenuated by superoxide dismutase, catalase and deferoxamine provides additional evidence to suggest that Se-induced oxidative stress mediates the induction of apoptosis, a mechanism related to the anti-carcinogenic and chemopreventive effect of Se.
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PMID:Sodium selenite-induced oxidative stress and apoptosis in human hepatoma HepG2 cells. 1032 39

In the standard model of cytokine-induced signal transducer and activator of transcription (STAT) protein family signaling to the cell nucleus, it is assumed that STAT3 is recruited to the cytoplasmic side of the cell surface receptor complex from within a cytosolic monomer pool. By using Superose-6 gel-filtration chromatography, we have discovered that there is little monomeric STAT3 (91 kDa) in the cytosol of liver cells (human hepatoma Hep3B cell line and rat liver). The bulk of STAT3 (and STAT1, STAT5a, and -b) was present in the cytosol as high molecular mass complexes in two broad distributions in the size range 200-400 kDa ("statosome I") and 1-2 MDa ("statosome II"). Upon treatment of Hep3B cells with interleukin-6 (IL-6) for 30 min (i) cytosolic tyrosine-phosphorylated STAT3 was found to be in complexes of size ranging from 200-400 kDa to 1-2 MDa; (ii) a small pool of monomeric STAT3 and tyrosine-phosphorylated STAT3 eluting at 80-100 kDa was observed, and (iii) most of the cytoplasmic DNA-binding competent STAT3 (the so-called SIF-A "homodimer") co-eluted with catalase at 230 kDa. In order to identify the protein components of the 200-400-kDa statosome I cytosolic complexes, we used the novel technique of antibody-subtracted differential protein display using anti-STAT3 antibody. Eight polypeptides in the size range from 20 to 114 kDa co-shifted with STAT3; three of these (p60, p20a, and p20b) were co-shifted in an IL-6-dependent manner. In-gel tryptic fragmentation and mass spectroscopy identified the major IL-6-dependent STAT3-co-shifted p60 protein as the chaperone GRP58/ER-60/ERp57. Taken together, these data (i) emphasize the absence of a detectable STAT3 monomer pool in the cytosol of cytokine-free liver cells as posited by the standard model, and (ii) suggest an alternative model for STAT signaling in which STAT3 proteins function in the cytoplasm as heteromeric complexes with accessory scaffolding proteins, including the chaperone GRP58.
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PMID:Cellular physiology of STAT3: Where's the cytoplasmic monomer? 1046 81

Farnesyl diphosphate synthase (FPPS: EC2.5.1.10), a key enzyme in isoprenoid metabolic pathways, catalyzes the synthesis of farnesyl diphosphate (FPP) an intermediate in the biosynthesis of both sterol and non-sterol isoprenoid end products. The localization of FPPS to peroxisomes has been reported (Krisans, S. K., J. Ericsson, P. A. Edwards, and G. A. Keller. 1994. J. Biol. Chem. 269: 14165;-14169). Using indirect immunofluorescence and immunoelectron microscopic techniques we show here that FPPS is localized predominantly in the peroxisomes of rat hepatoma H35 cells. However, the partial release of 60;-70% of cellular FPPS activity is observed by selective permeabilization of these cells with digitonin. Under these conditions, lactate dehydrogenase, a cytosolic enzyme, is completely released whereas catalase, a known peroxisomal enzyme, is fully retained. Digitonin treatment of H35 cells differentially affects the release of other peroxisomal enzymes involved in isoprenoid metabolism. For instance, mevalonate kinase and phosphomevalonate kinase are almost totally released (95% and 91%, respectively), whereas 3-hydroxy-3-methylglutaryl-CoA reductase is fully retained. Indirect immunoflourescence studies indicate that FPPS is localized in peroxisomes of Chinese hamster ovary (CHO)-K1 cells but is dispersed in the cytosol of ZR-82 cells, a mutant that lacks peroxisomes. Unlike in H35 cells, FPPS is completely released upon digitonin permeabilization of CHO-K1 and ZR-82 cells. In contrast, under the same permeabilization conditions, catalase is fully retained in CHO-K1 cells but completely released from ZR-82 cells. These studies indicate that FPPS and other enzymes in the isoprenoid biosynthetic pathways, involved in the formation of FPP, are differentially associated with peroxisomes and may easily diffuse to the cytosol. Based on these observations, the significance and a possible regulatory model in the formation of isoprenoid end-products are discussed.
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PMID:Differential binding of proteins to peroxisomes in rat hepatoma cells: unique association of enzymes involved in isoprenoid metabolism. 1048 4


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