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)

Reuber (H35) hepatoma cells were grown in medium containing 10(-5)M bromodeoxyuridine (BrdU), which was incorporated into their DNA. Cell growth rate was unaffected by BrdU for the first two generations, after which it was reduced by about 50%. The effect of BrdU incorporation on the activities of several enzymes with rapid turnover rates was examined to test the hypothesis that the synthesis of such enzymes will be preferentially inhibited by BrdU. Tyrosine amino-transferase (TAT) activity decreased by 70% within two generations whereas thymidine kinase activity remained at control values. PEP carboxykinase activity was unchanged during the first generation in BrdU-containing medium but, during the second, its activity increased by at least 30%. Ornithine decarboxylase levels decreased by about 50% only after two generations in the presence of BrdU. There appeared to be no simple relationship between turnover rates and the effect of BrdU on enzyme activity. Incorporation of BrdU was found to inhibit the induction of both TAT and PEP carboxykinase by dexamethasone and to enhance the inhibition of cell growth by this steroid. These results are discussed with respect to possible mechanisms of gene expression and development in both normal and neoplastic cells.
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PMID:The diverse effects of 5'-bromodeoxyuridine on enzyme activities in cultured H35 hepatoma cells. 1 36

Quiescent, contact inhibited H-35 rat hepatoma cell cultures maintained in minimal essential medium contain a very low level of ornithine decarboxylase activity. However, 2 h after the addition of 10% fetal calf serum to the culture medium, the enzyme activity increases by approx. 100-fold. This increase can be completely inhibited by the simultaneous addition of 10(-2) M putrescine. The presence of putrescine elicits the appearance of an intracellular inhibitor of ornithine decarboxylase. This inhibitor of ornithine decarboxylase has a molecular weight of 26500, is sensitive to the action of chymotrypsin and is noncompetitive with respect to ornithine. The intracellular appearance of this inhibitor is sensitive to cycloheximide but is only partially inhibited by actinomycin D.
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PMID:The appearance of an ornithine decarboxylase inhibitory protein upon the addition of putrescine to cell cultures. 17 75

Ornithine decarboxylase has been induced in log phase hepatoma cells grown in suspension culture. Induction with N6, O2'-dibutyryl cyclic adenosine 3':5'-monophosphate produced a 4-fold increase in enzyme activity by 3 hours which was followed by a return to base levels by 6 hours. Induction with dexamethasone, a potent synthetic glucocorticoid, exhibited a slow steady rate of increase in enzyme activity, reaching a plateau level of approximately 5- to 6-fold stimulation by about 12 hours. Induced cell and regenerating rat liver ornithine decarboxylase were shown to be indistinguishable by titration with antibody monospecific to the latter and by heat stability. L-[14C]Leucine incorporation into immunoprecipitable enzyme protein after induction in vitro or partial hepatectomy showed an increase which, when coupled with the increase in enzymatic activity, indicated de novo synthesis of enzyme protein. Physiological concentrations of the naturally occurring polyamines, spermidine and spermine, abolish cyclic AMP induction whereas they have no effect on dexamethasone induction. Both inductions were abolished by cycloheximide; in contrast, inhibition by actinomycin D was complete for dexamethasone induction and only partial with respect to cyclic AMP induction. The different time pattern of induction seen with cyclic AMP and dexamethasone, the partial inhibition of the cyclic AMP induction seen with actinomycin D, as well as the absence of inhibition of the dexamethasone induction by polyamines, indicate that these inducers might affect different aspects of the control of the same enzyme.
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PMID:Stimulation of ornithine decarboxylase synthesis and its control by polyamines in regenerating rat liver and cultured rat hepatoma cells. 18 26

Exogenous diamines and polyamines added to rat hepatoma (HTC) cells in culture rapidly decrease ornithine decarboxylase (ODC) activity. Previous evidence has suggested that these amines set either at the level of blocking new enzyme synthesis or by the induction of a non-competitive protein inhibitor, termed antizyme, which complexes with ODC to form an inactive complex. Wth the use of HMOA cells, a recently cloned rat hepatoma cell line that has a greatly stabilized ODC, it has been possible to demonstrate that 10(-5) M of exogenous putrescine blocks the increase in ODC activity, but unlike in the parent HTC cell line, without induction of the antizyme or formation of any inactive ODC-antizyme complex. However, complete blockade of ODC at 10(-2) M putrescine is effected by induction of antizyme and formation of the ODC-antizyme complex, as now evidenced by the isolation of the active enzyme and antizyme components after Sephadex column chromatography in the presence of 250 mM NaCl. These findings indicate clearly that two polyamine-regulatory mechanisms for ODC exist and are separable in this cell line.
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PMID:Two distinct mechanisms for ornithine decarboxylase regulation by polyamines in rat hepatoma cells. 45 86

GABA added to rat hepatoma (HTC) cells in spinner culture at the time of induction of cell proliferation increased levels of ornithine decarboxylase (ODC) up to two- to threefold above that of control cells. The increases in ODC were also reflected by concomitant increases of intracellular putrescine levels, while spermidine and spermine were unchanged. GABA seems to have a direct stabilizing effect on ODC, since the turnover of the enzyme was slowed almost twofold when measured in cells treated with 10(-2) M GABA. The stabilizing effect is most pronounced for GABA, although some amino acids such as asparagine, glutamine, and lysine as well as some GABA analogues and homologues also tend to increase ODC but to a significantly lesser extent than GABA itself. GABA metabolites had no effect on ODC. S-Adenosylmethionine decarboxylase and tyrosine aminotransferase were not affected by the presence of GABA. The GABA effect on ODC may be important in certain types of cells for the regulation of polyamine biosynthesis.
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PMID:Regulatory interrelations between GABA and polyamines. II. Effect of GABA on ornithine decarboxylase and putrescine levels in cell culture. 48 79

A biphasic increase of putrescine concentration occurs in rat hepatoma tissue culture cells induced to proliferate. DL-alpha-Methyl ornithine, a competitive inhibitor of ornithine decarboxylase ( L-ornithine carboxylyase, EC 4.1.1.7) of hepatoma tissue culture cells, blocks the usual increases of putrescine and spermidine concentrations in these cells, and causes a rapid fall in the levels of putrescine which is followed by a striking decrease of spermidine. In parallel with the depletion of these amines, incorporation of [3H]thymidine into DNA and cell proliferation are inhibited. Addition of putrescine, spermidine, or spermine results in an immediate resumption of cell proliferation. Cell proliferation is also restored by L-ornithine presumably due to in situ competitive inhibition of ornithine decarboxylase. These findings of hepatoma tissue culture cells support the concept that polyamines play an essential function in the cell division processes.
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PMID:Alpha-methyl ornithine, a potent competitive inhibitor of ornithine decarboxylase, blocks proliferation of rat hepatoma cells in culture. 106 34

We have investigated the biochemical basis of the mevalonate dependence of DNA replication. Stimulating quiescent rat hepatoma cells to proliferate in the presence of compactin, an inhibitor of mevalonate synthesis, prevented DNA replication in as many as 80% of these cells. The percentage of cells that failed to replicate DNA increased with the increased duration of quiescence. Aphidicolin-sensitive DNA polymerase and ornithine decarboxylase activities were selectively decreased in compactin-treated cells, whereas RNA and protein synthesis, the level of dihydrofolate reductase and aphidicolin-resistant DNA polymerase activity were unaffected. Adding putrescine, the product of ornithine decarboxylase and the precursor of other polyamines, did not restore DNA replication. Our results demonstrate that the decreased activities of at least two DNA-replication enzymes are among the proximal causes of the failure of mevalonate-deprived cells to synthesize DNA. More importantly, our data indicate that a mevalonate-dependent factor(s) is progressively depleted during quiescence, and that inability to resynthesize this factor(s) may be the ultimate cause of the failure of resting cells to replicate DNA when stimulated to proliferate in the absence of mevalonate.
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PMID:The effect of mevalonic acid deprivation on enzymes of DNA replication in cells emerging from quiescence. 128 82

Ornithine decarboxylase (ODC) has been shown by biochemical analysis, to be important for cell proliferation and carcinogenesis in a variety of tissues, including the liver. We detected messenger RNA (mRNA) specific for the enzyme ODC in 18 patients with hepatocellular carcinoma by an in situ hybridization technique using a radiolabelled ODC probe on formalin-fixed liver specimens. Adjacent uninvolved liver tissues were used as controls. Among the adjacent uninvolved liver tissues, five showed evidence of cirrhosis. Poorly differentiated hepatocellular carcinoma has significantly higher levels of ODC mRNA than does well-differentiated hepatocellular carcinoma, which in turn has a significantly higher ODC mRNA level than adjacent uninvolved liver tissues; tissues showing evidence of cirrhosis, on the other hand, had a significantly lower ODC mRNA level than adjacent uninvolved liver tissue. This pattern of ODC gene expression in hepatocellular carcinoma is similar to the pattern of expression of other oncogenes in liver tumours. The quantitative detection of ODC mRNA in hepatocellular carcinoma by in situ hybridization may help elucidate the potential role of ODC in hepatocarcinogenesis.
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PMID:Detection of ornithine decarboxylase messenger RNA in human hepatocellular carcinoma by in situ hybridization. 133 80

The effects of inhibitors of polyamine synthesis on the invasive capacity of rat ascites hepatoma (LC-AH) cells were examined by in vitro assay of penetration of the LC-AH cells through a monolayer of calf pulmonary arterial endothelial (CPAE) cells. Pretreatment of LC-AH cells with alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, before seeding them onto a CPAE cell monolayer and culturing them for 24 h in the absence of DFMO decreased the number of penetrating tumor cells time and dose dependently (about 35% of the maximal inhibition) without affecting their viability or proliferative activity. DFMO treatment caused a marked decrease in the intracellular level of putrescine but not of spermidine or spermine. The DFMO-induced decreases in invasive capacity and putrescine level were almost completely reversed by the addition of putrescine to the medium during pretreatment with DFMO or invasion assay but were not affected by exogenous spermidine or spermine. No change in the invasive capacity was observed when the CPAE cells were treated with DFMO and the LC-AH cells with methylglyoxal-bis(guanylhydrazone), an inhibitor of S-adenosylmethionine decarboxylase, which depressed the spermidine and spermine levels but increased the putrescine level in the LC-AH cells. These results suggest that intracellular putrescine modulates the in vitro invasive capacity of LC-AH cells.
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PMID:Putrescine-dependent invasive capacity of rat ascites hepatoma cells. 139 36

The activity of ornithine decarboxylase (ODC) in H-35 hepatoma cells depleted of Ca2+ by washing with 2 mM EGTA increased 35-fold after incubating for 4 h in a simple salt-glucose solution containing 10 mM L-asparagine and only if Ca2+ was replenished. Actinomycin D (5 micrograms/ml) and cycloheximide (20 microM) reduced the stimulatory effect by 84 and 100% respectively. Increase of active enzyme protein was also demonstrated by a 3-fold increase in alpha-difluoromethylornithine binding. Asparagine prolonged the half-life of induced ODC by 20% whereas Ca2+ reduced it by 32%. The observed inductive effects are not accounted for entirely by a direct influence of Ca2+ and asparagine on the turnover of ODC protein. These factors are likely to be parts of a signalling pathway leading to amplification of cellular ODC.
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PMID:Relationship between Ca2+ and L-asparagine in the induction of ornithine decarboxylase in H-35 rat hepatoma cells. 144 90


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