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)

Cross-resistance to a wide array of toxic chemicals is a common phenomenon in cisplatin-resistant cell lines. In this study, two independently isolated cisplatin-resistant cell lines derived from a human hepatoma and a cervical adenocarcinoma were shown to be cross-resistant to methotrexate (MTX) and several metal salts, such as sodium arsenite, sodium arsenate, antimony potassium tartrate, and cadmium chloride. A pleiotropic defect resulting in reduced accumulation of cisplatin, 3[H]MTX, 73As3+, and 73As5+ was found in both cisplatin-resistant cell lines. Analysis by immunoblot, indirect immunofluorescence, and Northern hybridization showed dramatically reduced expression of the folate binding protein that mediates MTX uptake in both human cisplatin-resistant cell lines. By photoaffinity labeling with UV irradiation, specific binding proteins of Mr 230,000 and Mr 48,000 for 73As3+ and Mr 190,000 for 73As5+ were found in enriched plasma membrane of both human cisplatin-sensitive parental cell lines. Expression of these specific binding proteins was decreased in cells selected for cisplatin resistance. A protein band at Mr 36,000 that binds to 73As3+ was overexpressed in both human cisplatin-resistant cell lines. The finding of loss of distinct binding proteins for MTX, arsenate, and arsenite in association with decreased accumulation of these agents in cisplatin-resistant cells suggests a pleiotropic, possibly regulatory, alteration in these cells.
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PMID:Cross-resistance to methotrexate and metals in human cisplatin-resistant cell lines results from a pleiotropic defect in accumulation of these compounds associated with reduced plasma membrane binding proteins. 944 4

The rat hepatoma cell line McA RH7777 was cloned into alpha-fetoprotein-producing (AFP+) and non-producing (AFP-) sublines. A monoclonal antibody (MAb A2/3) reacting with an antigen (Ag A2/3) present only in AFP- clones or AFP- cells in mixed clones was obtained. Ag A2/3 was absent from the liver of embryonic, fetal, newborn and adult rats, but it was present in gastric and intestinal mucosa of adult rats. Ag A2/3 was found to be a heavy metal-inducible protein: Cd2+ and Pb2+ strongly induced the expression of Ag A2/3 in vivo in the liver of adult rats, while xenobiotics and CCl4 were not active in this respect. In vitro Cd2+ and Pb2+ induced Ag A2/3 expression in several AFP+ clones, leading to a simultaneous marked decrease of AFP+ cells from such clones. The effect of Cd2+ in the induction of Ag A2/3 and suppression of AFP was reversible. SDS PAGE revealed one protein band with an m.w. close to 45,000, which was not sensitive to mercaptoethanol. Despite its inducible properties, Ag A2/3 was shown not to belong to metallothioneins, cytochrome P-450, glutathion-transferase or heat shock proteins families, well-known as being inducible cell stress proteins. Expression of Ag A2/3 could be one of the factors determining the high amplitude of AFP production by individual liver tumors. The nature of Ag A2/3 and its alternative expression with respect to AFP remain to be studied.
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PMID:Inducible protein in rat hepatomas with expression alternative to alpha-fetoprotein. 945 96

Heme oxygenase-1 is an inducible enzyme that catalyzes heme degradation and has been proposed to play a role in protecting cells against oxidative stress-related injury. We investigated the induction of heme oxygenase-1 by the tumor promoter arsenite in a chicken hepatoma cell line, LMH. We identified a heme oxygenase-1 promoter-driven luciferase reporter construct that was highly and reproducibly expressed in response to sodium arsenite treatment. This construct was used to investigate the role of mitogen-activated protein (MAP) kinases in arsenite-mediated heme oxygenase-1 gene expression. In LMH cells, sodium arsenite, cadmium, and heat shock, but not heme, induced activity of the MAP kinases extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. To examine whether these MAP kinases were involved in mediating heme oxygenase-1 gene expression, we utilized constitutively activated and dominant negative components of the ERK, JNK, and p38 MAP kinase signaling pathways. Involvement of an AP-1 site in arsenite induction of heme oxygenase-1 gene expression was studied. We conclude that the MAP kinases ERK and p38 are involved in the induction of heme oxygenase-1, and that at least one AP-1 element (located -1576 base pairs upstream of the transcription start site) is involved in this response.
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PMID:Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. Role of mitogen-activated protein kinases. 953 75

Ions of metals such as mercury, cadmium and copper are known to exhibit a high affinity for thiol groups and may therefore severely disturb many metabolic functions in the cell. The aim of the present study was to identify the most sensitive changes of thiol metabolism induced by the addition of low concentrations of metal ions in order to elucidate the mechanisms of metal-toxicity. The effects on thiol metabolism by copper ions seemed to differ from that of mercury and cadmium ions. Copper ions exhibited mainly two effects that were different from those of mercury and cadmium ions. They lowered the reduced fractions of thiols and increased the release of homocysteine into the medium, whereas mercury and cadmium ions mainly influenced the metabolism of glutathione by increasing its synthesis. Even 0.1 micromol/l of copper ions increased the release of homocysteine in HeLa cell lines. An increased cellular concentration of glutathione and an increased release of glutathione into the medium were observed after addition of mercury and cadmium ions at a concentration of 1 micromol/l, which is just above the toxicity limit in human blood. The different cell lines varied in some respects in their response to the addition of metal ions. Cadmium ions had no effect on thiol metabolism in endothelial cell lines, and copper ions did not significantly increase the release of homocysteine into the medium in hepatoma cell lines. Furthermore, the metabolism of thiols during basal conditions (without the addition of metal ions) differed somewhat in the three cell lines investigated. One example is the low amount of extracellular glutathione in hepatoma cell lines, which probably was due to its rapid degradation to cysteinylglycine by gamma-glutamyl-transpeptidase.
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PMID:Alterations of thiol metabolism in human cell lines induced by low amounts of copper, mercury or cadmium ions. 967 68

In this paper, the pattern of induction of heat shock proteins (hsps) was studied in cultured Reuber H35 rat hepatoma cells by sequential application of different stressors. We analyzed whether a specific stress condition is able to induce an enhanced sensitivity to a subsequent application of a low dose of either the same or another stressor (self-sensitization and cross-sensitization, respectively). As a measure of sensitization, the stimulation of hsp induction was employed. Three different stressor conditions (heat shock, sodium arsenite and cadmium chloride) were used in doses which exerted a similar impact on overall protein synthesis. A synergistic effect in induction of the synthesis of various hsps was observed when a high stressor dose was followed by an 8-h incubation in a lower stressor dose in both self- and cross-sensitization experiments. The low-dose conditions used as second treatments did not induce any responses in non-pretreated cells. Studies in cultured cells have demonstrated stressor-specific hsp induction patterns. In this study we analyzed whether the pattern of hsps induced by the low-dose condition is characteristic for the first sensitizing stressor or for the secondary stressor applied in a low dose. The pattern of hsps which was induced above the level of the high-dose effect, due to the incubation with the secondary applied low-dose condition, was found to be characteristic for the secondary stressor and not for the sensitizing primary treatment. These results are of importance for an improved understanding of the regulation of heat shock protein synthesis in conditions of self- and cross-sensitization, as well as for a proper use of hsps as biomarkers of exposure to environmental stress.
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PMID:Stressor-specific enhancement of hsp induction by low doses of stressors in conditions of self- and cross-sensitization. 969 98

The gene expression of heme oxygenase-1 (HO-1) was studied in mammalian cell lines exposed to hyperoxia. Northern blot analysis demonstrated that hyperoxic exposure increased the HO-1 mRNA levels in various types of cells, including human hepatoma (HepG2) cells. This increase was time- and dose-dependent, and reversible. The HO-1 mRNA levels in HepG2 cells were increased to 2.3- and 4.2-fold of the control by hyperoxic exposure of 6 and 23 h, respectively. Cycloheximide and actinomycin D inhibited the increases in the HO-1 mRNA level produced by hyperoxia, indicating that response to hyperoxia is dependent on de novo protein synthesis and mRNA transcription. Antioxidants, desferrioxamine (DES) and o-phenanthroline (OP) partially inhibited the HO-1 mRNA elevation by hyperoxia. In addition to hyperoxia, sodium arsenite (NaAsO2), cadmium chloride (CdCl(2)) and hydrogen peroxide (H2O2), which are reactive oxygen intermediates (ROI) generators, increased the HO-1 mRNA level by 11-, 22- and 2.5-fold, respectively. OP, an antioxidant and a bivalent metal chelator, blocked the HO-1 mRNA elevation induced either by hyperoxia or by the three ROI generators. In contrast to OP, N-acetylcysteine (NAC), an antioxidant and membrane-permeable reducing reagent, enhanced the HO-1 mRNA elevation induced by hyperoxia, although NAC inhibited the mRNA elevation induced by NaAsO2, CdCl2 and H2O2. These results indicate that oxygen tension regulates HO-1 gene expression and suggest that hyperoxia-specific and redox-sensitive regulators may be involved in hyperoxia-mediated HO-1 gene expression.
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PMID:Oxygen tension regulates heme oxygenase-1 gene expression in mammalian cell lines. 974 10

The roles of the bHLH-Zip protein, upstream stimulatory factor (USF), in mouse metallothionein-I (MT-I) gene expression were examined. The promoter contains a putative USF binding site which overlaps an antioxidant response element (ARE) located at -101 bp relative to the transcription start point. The USF/ARE composite element increases basal expression of the mouse MT-I gene, and partly mediates response to oxidative stress. However, other functions of this composite element and the in vivo roles for USF in MT-I promoter functions have not been examined. We report studies which indicate that USF participates via the USF/ARE element in cadmium responsiveness of the mouse MT-I promoter. During the course of these studies a second, higher affinity USF binding site at -223 bp was identified. Stable and transient transfection assays in mouse hepatoma cells, using the USF/ARE in the context of a minimal promoter and site-directed and truncation mutants of the MT-I promoter, revealed that the USF and the ARE sites contribute to cadmium (2-30 microM) but not zinc responsiveness, and to basal promoter activity. Overexpression of dominant-negative (dn)USF in co-transfection assays significantly attenuated cadmium induction of the USF/ARE in the context of a minimal promoter, and attenuated cadmium, but not zinc, induction of the intact MT-I promoter. A consensus E-box (CACATG) at -223 bp in the MT-I promoter was also found to bind USF in vitro , and to be constitutively footprinted in vivo . The interaction of USF with E-box1 was apparently 10-fold stronger than that with the USF/ARE. However, in contrast, E-box1 was not a strong basal promoter element nor was it metal ions responsive in mouse Hepa cells. In conclusion, these studies demonstrate a role for USF in cadmium-specific induction of the mouse MT-I gene, but bring into question an obligate role for USF in regulating basal activity of this gene. The data further suggest that USF interacts with ARE-binding proteins to influence MT-I gene expression.
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PMID:Participation of upstream stimulator factor (USF) in cadmium-induction of the mouse metallothionein-I gene. 980 17

Human hepatoma cells (HepG2) were exposed to several heavy metal salts and the induction of heat shock protein 70 (hsp70) mRNA was analysed by the reverse transcriptase-polymerase chain reaction (RT-PCR). Metals were added to the cell medium at concentrations ranging from 0.1 to 100 microM and incubation was continued for 4 h. In addition we analysed the time dependence of hsp70 induction by adding each metal at a certain concentration followed by an incubation for 0.5 to 24 h. CdCl2, NaAsO2, AgNO3 could be classified as very strong inducers (20-, 13- and 10-fold above control level) and they reached their maximum level of induction at 1-10 microM after 2 h. CuCl2, MnCl2, Pb(NO3)2, TlNO3, CoCl2 and NiCl2 were also strong inducing agents, giving a 4-6 fold induction at 10-100 microM after 4-8 h. ZnSO4, Hg(NO3)2 and AlCl3 were only weak inducers (1.5-2 fold at 50-100 microM after 4-8 h) of hsp70 mRNA. Cytotoxic effects (measured by release of lactate dehydrogenase) could only be detected for 100 microM Hg2+ after 4 h and when the cells were incubated with 5 microM Cd2+ for more than 8 h. We also tested a few combinations of these heavy metal salts for their hsp70-inducing ability. Zn2+ and Mn2+ were able to diminish Cd2+ induced hsp70 mRNA levels by 65%. Ag+ mediated induction was reduced by 40% when combined with Cu2+, whereas Hg2+ increased induction by Ag+ about 3-fold and led to a dramatic decrease in cell viability. In our study we were able to demonstrate that the analysis of hsp70 mRNA levels in chemically stressed HepG2 cells by RT-PCR can be a valuable tool for studying mechanisms of toxicity associated with elevated expression of hsp70.
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PMID:Analysis of hsp70 mRNA levels in HepG2 cells exposed to various metals differing in toxicity. 982 Jun 63

A brief and moderate heat shock to Reuber H35 hepatoma cells causes a rapid increase in the synthesis of heat shock proteins (hsp) and initiates the development of thermotolerance, which results in an increased ability to survive exposure to otherwise lethal temperatures. We now demonstrate that low doses of various chemical stressors (arsenite, cadmium, mercury, lead, copper, menadione and diethyldithiocarbamate (ddtc)), at concentrations that do not exert any effect in control cultures, are able to enhance the synthesis of hsps and to stimulate the development of thermotolerance when applied to cultures which were pretreated with a mild heat shock. The degree of stimulation appears to be stressor-specific, which is not only observed in the ensuing development of thermotolerance but also in the enhancement of the heat shock-induced synthesis of stress proteins. The different hsps that show an enhanced induction when heat shocked cultures are exposed to the various secondary applied low doses of chemical stressors, were found to resemble the hsp pattern that is characteristic for the secondary stressor and not for the initial heat shock. In other words, the nature of the post-treatment determines the observed pattern of enhanced synthesis of hsps. In order to analyze the origin of the stimulation of survival capacity by low doses of the mentioned stressors, we studied whether the degree of stimulation is determined by the degree of similarity between the overall stress response to heat shock and to the second stress condition when applied singly. The degree in which low doses of chemical stressors stimulate tolerance development and enhance the synthesis of hsps in cells that were previously heat shocked, appears to be related to the degree of similarity in the hsp pattern induced by both stressors. Our results support the notion that low doses of toxic compounds may, under certain conditions, have beneficial effects related to a stimulation of endogenous cytoprotective mechanisms.
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PMID:Stimulation of survival capacity in heat shocked cells by subsequent exposure to minute amounts of chemical stressors; role of similarity in hsp-inducing effects. 1045 79

The Cu/Zn superoxide dismutase (SODI) catalyzes the dismutation of superoxide radicals produced in the course of biological oxidations. When placed under the control of the rat SOD1 gene promoter and transfected into human HepG2 hepatoma cells, the activity of a chloramphenicol acetyltransferase reporter gene was found to increase three- to four-fold in the presence of heavy metals (cadmium, zinc and copper). Functional analysis of mutant derivatives of the SOD1 gene promoter and the use of a heterologous promoter system confirmed that the induction of the SOD1 gene by metal ions requires a metal-responsive element (MRE) located between positions -273 and -267 (GCGCGCA). It was also shown by gel mobility shift assays that an MRE binding protein is induced by the exposure of the human liver cell line HepG2 to heavy metals. These results suggest that the MRE participates in the induction of the SOD1 gene by heavy metals.
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PMID:Heavy metal-mediated activation of the rat Cu/Zn superoxide dismutase gene via a metal-responsive element. 1051 27


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