Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 ability of isoproterenol, glucagon, PGE1 and cholera toxin to stimulate the synthesis of cAMP and protein kinase activity in line of liver cells (BRL) and a line of rat hepatoma cells (H35) has been determined. The concentration of cAMP in BRL cells (approximately 10 pmoles/mg protein) is in the range reported for other cultured cell lines but H35 cells contain extraordinarily low amounts of this cyclic nucleotide (approximately 0.05 pmoles/mg protein). Isoproterenol and PGE1 caused an increase in cAMP content, and protein kinase activation in BRL cells, although glucagon was ineffective. H35 cells, in contrast, were completely insensitive to all hormonal agonists. Despite this fact, cholera toxin was able to produce a marked increase in cAMP content, adenylate cyclase activity and protein kinase activation in H35 cells. binding studies with [125 I]-iodohydroxybenzylpindolol, a specific beta-adrenergic receptor antagonist, revealed that each H35 cell possesses fewer than 10 beta-adrenergic receptors whereas BRL cells contain 2-5,000 receptors per cell. The low level of cAMP in H35 cells appears to result from a combination of totally unstimulated adenylate cyclase and apparently elevated phosphodiesterase activities.
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PMID:Studies of cAMP metabolism in cultured hepatoma cells: presence of functional adenylate cyclase despite low cAMP content and lack of hormonal responsiveness. 20 52

The antitumour agent 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) was found to inhibit competitively the low-Km cyclic AMP phosphodiesterase activity in an ammonium-sulphate-precipitable fraction of the 2,000g supernatant of rat liver. With substrate concentration at 0.25 microM, I50 was 790 microM for DTIC and 350 microM for theophylline. DTIC at 2 mM more than doubled the cAMP response to glucagon in hepatocytes and to adrenaline in MH1C1 hepatoma cells, indicating that it also exerts its inhibitory effect on the phosphodiesterase in intact cells. The possible contribution of the phosphodiesterase inhibition to the growth-inhibitory and cytotoxic effects of DTIC is discussed.
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PMID:The antitumour agent 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) inhibits rat liver cAMP phosphodiesterase and amplifies hormone effects in hepatocytes and hepatoma cells. 22 92

A variety of 6- and 8-substituted analogs of cAMP (cyclic adenosine 3:5-monophosphate) have been tested for their ability to increase activity of tyrosine aminotransferase (EC 2.6.1.5) in cultured Reuber H35 hepatoma cells. Some analogs, particularly the 8-thio-substituted ones, produced effects approximately equivalent to those generated by N-6, O2'-dibutyryl cAMP. In contrast, cAMP and its O-2-monobutyryl derivative were relatively ineffective even at very high concentrations, whereas three other analogs actually depressed the activity of the aminotransferase. Changes in enzyme activity generated by the various analogs were paralleled closely by changes in the relative rate of aminotransferase synthesis. An excellent correlation was found to exist between the ability of any given analog to influence the activity of tyrosine aminotransferase and that of phosphoenolpyruvate carboxykinase (EC 4.1.1.32). A similar correlation was found to exist between the ability of various analogs to evelate the activity of these enzymes and to inhibit reversibly the growth of H35 cells. Only one of five inhibitors of cAMP phosphodiesterase activity tested produce any increase in aminotransferase activity when added alone. All of the 6- and 8-substituted analogs tested, including noniducers, stimulated f1 histone phosphorylation in crude rat liver extracts with approximately equal potencies. On the other hand, dibutyryl cAMP was only a weak activator of protein kinase in vitro, even though it is a potent enzyme inducer. A possible resolution of this apparent discrepancy has been provided by preliminary analyses of site-specific f1 histone phosphorylation in whole cells. Only compounds active as aminotransferase inducers are capable of stimulating phosphorylation of the serine-37 residue of endogenous f1 histone (3- to 10-fold).
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PMID:Effects of 6- and 8-substituted analogs of adenosine 3':5'-monophosphate on phosphoenolpyruvate carboxykinase and tyrosine aminotransferase in hepatoma cell cultures. 23 87

When supernatants of thymic epithelial cell cultures (STEC) or thymosin fraction 5 were incubated with washed platelets (37 degrees C for 30 min), the levels of platelet guanosine 3',5'-cyclic monophosphate (cyclic GMP) were increased in a dose-dependent manner. In contrast the supernatants from Chang, HeLa, or HCC-M cell cultures did not significantly affect the levels of intracellular cyclic GMP. The increment of intracellular cyclic GMP levels following treatment with STEC increased with longer incubation times until a plateau was reached at 30 min. This activity of STEC was found in fractions with a molecular weight below 10,000 daltons. Contents of guanine and guanosine in STEC were lower than those observed in other culture supernatants. STEC did not affect guanylate cyclase activity in platelets, but significantly inhibited cyclic GMP phosphodiesterase activities in platelet soluble and membrane fractions. Thymosin fraction 5 inhibited the phosphodiesterase activity of the soluble but not the membrane fraction.
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PMID:In vitro effect of thymic epithelial culture supernate on cyclic GMP levels in rabbit platelets. 197 Jun 75

Several studies have found high cAMP content in hepatomas in vivo, while hepatoma cells in vitro have very low levels. To explore this discrepancy and the regulation of cAMP in hepatomas, we have examined the cell line MH1C1 from Morris hepatoma 7795. These cells in culture contained low intracellular cAMP concentrations (approximately 0.5 pmol/mg protein at confluency), and were unresponsive to glucagon and prostaglandins (PG) E1 and E2. In contrast, solid hepatomas in rats developed from inoculates of MH1C1 had a 40-fold higher basal cAMP concentration and were stimulated by PGE1 and PGE2. Fibroblasts cultured from these tumours also contained high cAMP levels and responded strongly to PGE1. This may suggest that the difference in cAMP regulation between hepatomas in vivo and hepatoma cells in vitro results from the presence of other cells in the solid tumour rather than from selection of low-cAMP cells during the cloning procedure. Low-Km and intermediate-Km cAMP phosphodiesterase activity was high in MH1C1, compared to normal hepatocytes. This might contribute to the low cAMP level. The ability of MH1C1 to form cAMP was not defective, as the level could be increased more than 200-fold by beta-adrenergic activation in the presence of the phosphodiesterase inhibitor methylisobutylxanthine.
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PMID:The regulation of cyclic AMP levels in cultured MH1C1 rat hepatoma cells and in solid tumours derived from MH1C1 cell inoculates. 303 96

The effect of dexamethasone on adenosine 3',5'-monophosphate (cAMP) phosphodiesterase activity in cultured HTC hepatoma cells was investigated. Homogenates of these cells contain phosphodiesterase activity with two apparent Michaelis constants for cAMP (2-5 mum and 50 mum). At all substrate concentrations tested, phosphodiesterase activity was decreased 25-40% in cells incubated for 36 hr or more with 1 mum dexamethasone. Acid phosphatase activity in the same cells was not decreased. alpha-Methyl testosterone, 1 mum, was without effect on phosphodiesterase activity. Incubation for 10 min with epinephrine plus theophylline increased the cAMP content of the HTC cells 3- to 6-fold. In cells incubated for 72 hr with dexamethasone, the basal concentration of cAMP was slightly increased and the increment produced by epinephrine plus theophylline was markedly increased. We believe that in many cells the so-called permissive effects of steroid hormones on cAMP mediated processes may be due to an effect of these hormones on cAMP phosphodiesterase activity similar to that observed in HTC cells incubated with dexamethasone.
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PMID:An effect of dexamethasone on adenosine 3',5'-monophosphate content and adenosine 3',5'-monophosphate phosphodiesterase activity of cultured hepatoma cells. 434 39

The cAMP phosphodiesterase activity in mouse hepatomas 46, 61 and 22A is established to be lower than in the normal liver. Sensitivity of enzymes to inhibitors in tumours is also lower. Dibutyryl-cAMP inhibits the growth of hepatoma 46 and leads to an increase in the functional activity of tumour cells.
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PMID:[Adenosine cyclic-3',5'-monophosphate phosphodiesterase in hepatomas with different growth rates]. 609 46

The following evidence suggests that inhibition of hepatoma cell (HTC) growth by cyclic nucleotides is an adenosine-like effect that is greatly modified by the type and treatment of serum used in the culture medium and is probably not mediated by cyclic AMP-dependent protein kinase: 1) Heating serum reduces its phosphodiesterase content, thereby slowing metabolism of cyclic AMP and reducing the inhibition of HTC cell growth by cyclic AMP; 2) Using medium that contains phosphodiesterase but lacks adenosine deaminase causes adenosine to accumulate from cyclic AMP and increases the toxicity of cyclic AMP; 3) Uridine or cytidine reverses the growth inhibition caused by adenosine, 5'-AMP or cyclic AMP; 4) adenosine, 5'-AMP and N6-(delta 2-isopentenyl) adenosine are more toxic for HTC cells than is cyclic AMP, and N6,O2-dibutyryl cyclic AMP is not toxic; and 5) N6,O2'-dibutyryl cyclic AMP inhibits growth of Reuber H35 cells, but uridine prevents this inhibition of growth. We conclude that most, if not all, of the inhibitory effects of cyclic AMP and N6,O2'-dibutyryl cyclic AMP on HTc and Reuber H35 hepatoma cell growth are due to the generation of toxic metabolites.
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PMID:Inhibition of hepatoma cell growth by analogs of adenosine and cyclic AMP and the influence of enzymes in mammalian sera. 612 49

Incubation of rat hepatoma cells with cAMP derivatives stimulates cell-associated plasminogen activator activity 8- to 22-fold and extracellular plasminogen activator activity 30- to 1300-fold. This time- and concentration-dependent increase is enhanced by phosphodiesterase inhibitors. Dexamethasone, a synthetic glucocorticoid, decreases the plasminogen activator activity of these cells, probably through induction of an inhibitor. Paradoxically, dexamethasone, added simultaneously with cAMP derivatives causes a further 4-fold enhancement of the cAMP-mediated stimulation of plasminogen activator activity. Dexamethasone also alters the time course of cAMP-mediated enhancement of plasminogen activator activity: increased protease activity is detected at 4 hr in cells incubated with 8-bromoadenosine-3':5'-cyclic monophosphoric acid and 1-methyl-3-isobutylxanthine but not until 12 hr in cells incubated with dexamethasone as well. Glucocorticoids thus exert two separate and opposite effects on plasminogen activator activity: induction of an inhibitor and amplification of cyclic nucleotide action. Although permissive and synergistic effects of dexamethasone on cyclic nucleotide action have been reported previously, glucocorticoid regulation of plasminogen activator activity is unique in that the amplification of cyclic nucleotide effects by dexamethasone opposes its regulatory action toward a specific enzyme.
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PMID:Paradoxical effects of glucocorticoids on regulation of plasminogen activator activity of rat hepatoma cells. 617 95

Precultured mouse peritoneal macrophages were incubated with a microbial growth inhibitory lymphokine prepared from cell-free ascites of rat Zajdela hepatoma. Cyclic nucleotide metabolism was followed in parallel to experiments demonstrating inhibition of intracellular growth of Corynebacterium murium kutscheri. Maximum increase of cAMP, adenylate cyclase and cAMP-phosphodiesterase activities was found after 60 to 90 min, while inhibition of microbial growth was evident only after 2-3 h. Both effects showed concordant dose dependence. It is concluded that cAMP induces cellular metabolic changes which lead to inhibition of bacterial growth by macrophages.
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PMID:Effect of a microbial growth inhibitory factor on the cyclic nucleotide metabolism of peritoneal macrophages. 626 1


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