UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor pathway inhibitor (TFPI) is a plasma serine protease inhibitor that directly inhibits coagulation factor Xa and regulates blood coagulation via inhibition of factor VIIa-tissue factor enzymatic activity. We previously demonstrated that >90% of TFPI bound to a single population of low affinity binding sites on hepatoma cells (2 x 10(6) sites/cell, Kd = 30 nM), and, that following binding, the low density lipoprotein receptor-related protein (LRP) mediated TFPI uptake and degradation. We subsequently reported heparan sulfate proteoglycans (HSPGs) constitute a second receptor system involved in TFPI catabolism. In the present study, mouse embryonic fibroblasts heterozygous and homozygous-negative for disruption of the LRP gene were used to further examine the roles of LRP and HSPGs in TFPI endocytosis. We demonstrate that LRP is absolutely required for degrading 125I-TFPI. LRP heterozygous and homozygous-negative cells bind 125I-TFPI similarly, and the 39-kDa protein, an inhibitor of all known ligand interactions with LRP, does not alter 125I-TFPI binding to these cells. TFPI can be cross-linked to LRP on [35S]cysteine-labeled hepatoma and LRP-heterozygous cells but not LRP-negative cells. When HSPGs are blocked with protamine, 125I-TFPI binds in a 39-kDa protein-inhibitable manner to 41,000 high affinity sites/hepatoma cell (Kd = 2.3 nM). Blockade of HSPGs with protamine results in significantly more 125I-TFPI degradation by LRP-positive cells. TFPI can be cross-linked to LRP in the absence and presence of protamine. However, in the presence of protamine, relative to the total pool of cross-linked proteins, 5-fold more TFPI is cross-linked to LRP. Finally, we show TFPI inhibits 125I-alpha2-macroglobulin-methylamine binding to hepatoma cells and that carboxyl-terminal residues 115-319 of the 39-kDa protein inhibit both 125I-TFPI degradation and binding when binding conditions contain protamine. Together, our results suggest that while the majority of TFPI binds to cell surface HSPGs, LRP can function independently from HSPGs in the binding and uptake of TFPI.
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PMID:The low density lipoprotein receptor-related protein can function independently from heparan sulfate proteoglycans in tissue factor pathway inhibitor endocytosis. 882 19

We studied the effect of intracellular glutathione (GSH), which was known to conjugate readily with an alpha, beta-unsaturated carbonyl of 9-deoxy-delta 9,12-13,14-dihydroPGD2 (delta 12-PGJ2), on the cytotoxicity of delta 12-PGJ2. delta 12-PGJ2 caused DNA fragmentation in human hepatocellular carcinoma Hep 3B cells, which was blocked by cycloheximide (CHX). The delta 12-PGJ2-induced apoptosis was augmented by GSH depletion resulted from pretreatment with buthioninine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. On the contrary, N-acetyl-cysteine (NAC), a precursor of cysteine, elevated the GSH level and protected cells from initiating apoptosis by delta 12-PGJ2. Sodium arsenite, a thiol-reactive agent, also induced apoptosis, which was potentiated or attenuated by BSO or NAC treatment respectively. These results suggest that the apoptosis-inducing activity of delta 12-PGJ2 is due to thiol-reactivity and intracellular GSH modulates the delta 12-PGJ2-induced apoptosis by regulating the accessibility of delta 12-PGJ2 to target proteins containing thiol groups.
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PMID:Intracellular glutathione level modulates the induction of apoptosis by delta 12-prostaglandin J2. 887 36

The microsomal triglyceride transfer protein (MTP) is required for assembly and secretion of the lipoproteins containing apolipoprotein B (apoB): very low density lipoproteins and chylomicrons. Evidence indicates that the subclasses of these lipoproteins that contain apoB-48 are assembled in a distinct two-step process; first a relatively lipid-poor primordial lipoprotein precursor is produced, and then bulk neutral lipids are added to form the core of these spherical particles. To determine if either step is mediated by MTP, a series of clonal cell lines stably expressing apoB-53 and MTP was established in non-lipoprotein-producing HeLa cells. MTP activity in these cells was approximately 30%, and apoB secretion was 7-33% of that in HepG2 cells on a molar basis. Despite having robust levels of triglyceride and phospholipid synthesis, these cell lines, as exemplified by HLMB53-59, secreted >90% of the apoB-53 on relatively lipid-poor particles in the density range of 1.063-1.21 g/ml. These results suggested that coexpression of MTP and apoB only reconstituted the first but not the second step in lipoprotein assembly. To extend this observation, additional studies were carried out in McArdle RH-7777 rat hepatoma cells, in which the second step of apoB-48 lipoprotein assembly is well defined. Treatment of these cells with the MTP photoaffinity inhibitor BMS-192951 before pulse labeling with [35S]methionine/cysteine led to an 85% block of both apoB-48 and apoB-100 but not apoAI secretion, demonstrating inhibition of the first step of lipoprotein assembly. After a 30-min [35S]methioneine/cysteine pulse labeling and 120 min of chase, all of the nascent apoB-48 was observed to have a density of high density lipoproteins (1.063-1.21 g/ml), indicating that only the first step of lipoprotein assembly had occurred. The addition of oleic acid to the cell culture media activated the second step as evidenced by the conversion of the apoB-48 high density lipoproteins to very low density lipoproteins (d < 1.006 g/ml) during an extended chase period. Inactivation of MTP after completion of the first step, but before stimulation of the second step by the addition of oleic acid, did not block this conversion. Thus, inhibition of MTP did not hinder the addition of bulk core lipid to the primordial lipoprotein precursor particles, indicating that MTP is not required for the second step of apoB-48 lipoprotein assembly.
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PMID:Inhibition of the microsomal triglyceride transfer protein blocks the first step of apolipoprotein B lipoprotein assembly but not the addition of bulk core lipids in the second step. 895 51

In this study we examined the interactions of liver microsomes with the antibiotic calvatic acid and with structural analogues, some of which had shown antimicrotubular properties. These drugs decreased cytochrome P-450 content differently according to the substitutions on the azoxy function and the ethoxycarbonyl derivatives were found to be the most effective ones. The decrease in cytochrome P-450 could be prevented by addition of cysteine or GSH, suggesting an involvement of sulphydryl groups. Furthermore, chromatographic analyses showed that ethoxycarbonyl derivatives were completely metabolized, and this would explain the different behaviour of these compounds towards microtubular protein when they were incubated with purified bovine brain protein or with liver or hepatoma extracts.
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PMID:Interactions between calvatic acid and related compounds with rat liver microsomes. 898 28

Rhodostomin (RHO) from Agkistrodon rhodostoma venom, consisting of 68 amino acids with an arginine-glycine-aspartic acid (RGD) sequence and 12 cysteine residues, is a potent inhibitor of platelet aggregation. We previously demonstrated that cell culture plates coated with the bacterially produced fusion protein of glutathione S-transferase-RHO [GST-RHO(RGD)] can facilitate human hepatoma cell attachment via intergrin interaction within 15 min. In this study, we further characterized the effect of RHO fusion protein on platelet cells by creating two other related fusion proteins, GST-RHO(RGE) and GST-(PS)RHO. The former was a single amino acid-substituted mutant, in which the aspartic acid residue of RGD was replaced by glutamic acid, and the latter was an insertion mutant, in which a pentapeptide of protein kinase A phosphorylation site was inserted between GST and RHO. These two mutant proteins together with a wild-type of GST-RHO(RGD) and native form of RHO were used to study effects on the inhibition of ADP-induced platelet aggregation. Results indicated that GST-RHO(RGD) inhibited platelet aggregation as potently as the native RHO, while the two other mutants were inactive. Furthermore, when unactivated platelet cells attached on the GST-RHO(RGD)-coated plate, they became a flattened pancake shape. From the results of facilitation of cell attachment on fusion protein-coated plates, we concluded that: (1) the GST-RHO(RGD) fusion protein is equally functional in inhibition of platelet aggregation and facilitation of cell attachment, which is through the interaction of RGD and integrins on the cell membrane; (2) the GST-RHO(RGE) mutant protein is unable to bind with integrins and results in loss of function; (3) the insertion mutant of GST-(PS)RHO may disrupt a proper conformation of RHO and also results in loss of function; (4) the bacterially produced fusion protein GST-RHO(RGD) can be properly used as an antithrombotic agent and an extracellular matrix.
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PMID:Glutathione S-transferase-rhodostomin fusion protein inhibits platelet aggregation and induces platelet shape change. 908 May 76

The highest amount of N-acetylneuraminic acid (AcNeu) was found in pyruvate kinase isoenzyme L from normal rat liver (24 moles/mole of enzyme tetramer), with the highest electrophoretic mobility. On the other hand, isoenzyme M2 from Morris hepatoma 7777, with the lowest electrophoretic mobility, had the lowest AcNeu content (5 moles/mole of enzyme tetramer). This tumour isoenzyme M2 of pyruvate kinase was, however, characterised by the highest phosphate content (12 moles/mole protein), in comparison to isoenzyme L (3 moles/mole protein) or normal liver isoenzyme M2 (6 moles/mole protein). This could indicate a regulatory change caused by reversible enzyme phosphorylation and dephosphorylation or sialization and desialization. Despite these differences, the sum of the two negatively charged residues was lower in tumour pyruvate kinase isoenzyme M2, with the slowest migration rate, than in normal rat liver isoenzyme M2. Moreover, isoenzyme M2 from tumour material, in comparison with isoenzyme M2 from normal rat liver, had a twice as high content of thiol groups (20 moles/mole protein), especially of free and superficially located ones, than the isoenzyme M2 from normal liver (10 moles/mole protein). This may explain abnormal susceptibility of tumour isoenzyme M2 to stereospecific inhibition by exogenous L-cysteine, and indicate genetically dependent changes in amino-acid content of tumour enzyme which take place during cell tumourigenic transformation.
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PMID:N-acetylneuraminic acid, phosphate and thiol groups of pyruvate kinase isoenzymes from Morris hepatoma 7777 and normal rat liver. 936 Jul 8

The cytotoxic mechanism of a conjugate of doxorubicin (DXR) and glutathione (GSH) via glutaraldehyde (GSH-DXR) was investigated using DXR-sensitive (AH66P) and -resistant (AH66DR) rat hepatoma cells. GSH-DXR accumulated in AH66DR cells as well as in AH66P cells without efflux by P-gp and exhibited the potent cytocidal activity against both cells compared with DXR. To examine whether thiol from GSH-DXR affected the expression of cytotoxicity, two conjugates of DXR, with modified peptides containing alanine or serine substituted for cysteine in GSH were prepared and their cytotoxicities determined. Substitution of these amino acids for cysteine resulted in an approximately two- to fourfold reduction in cytotoxic activity against both cell lines compared with the effect of GSH-DXR. Depletion of intracellular GSH by treatment of both cells with buthionine sulphoximine did not change the cytotoxic activity of DXR, BSA-DXR or GSH-DXR. By co-treating the cells with tributyltin acetate, an inhibitor of glutathione S-transferase (GST), and either DXR, BSA-DXR or GSH-DXR, the cytotoxicity was markedly increased. Interestingly, GSH-DXR showed non-competitive inhibition of GST activity and its IC50 value was 1.3 microM. These results suggested that the inhibition of GST activity by GSH-DXR must be an important contribution to the expression of potent cytotoxicity of the drug.
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PMID:Glutathione-doxorubicin conjugate expresses potent cytotoxicity by suppression of glutathione S-transferase activity: comparison between doxorubicin-sensitive and -resistant rat hepatoma cells. 937 80

The rat hepatoma cell line H4-II-E was found to express much higher activities of Na+-dependent glutamine and aspartate transport than those observed in normal cultured hepatocytes, in agreement with previous work of others on human hepatocytes. Na+-dependent glutamine transport in rat hepatoma cells could be resolved into two components. One was pH-dependent, tolerated Li+ for Na+ substitution and was inhibited only by asparagine and histidine; characteristics similar to those of transport System N in hepatocytes. The other transport system had a similar Km for glutamine but was pH independent, did not accept Li+ ions and was completely inhibited by excess concentrations of lysine, histidine, leucine, serine and cysteine, but not by methyl-aminoisobutyrate or phenylalanine. This pattern of inhibition is distinct from that of any transporter occurring in normal hepatocytes and may indicate the presence of a new transporter isoform. Similar results were obtained with the cell line HTC. Na+-dependent aspartate transport in H4 hepatoma cells was mediated by a high-affinity system (Km 5 microM) and was inhibited by D-aspartate and L-glutamate but not by d-glutamate-properties characteristic of the high-affinity glutamate transporter EAAC1. C-terminal antibodies to the EAAC1 protein recognized a single band of 58 kDa in hepatocyte membranes, but an additional strong band of 60 kDa was present in H4 hepatoma cells. These results provide further evidence for the view that tumour cells may express additional isoforms of amino acid transport systems which are not present in non-transformed cells.
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PMID:Rat hepatoma cells express novel transport systems for glutamine and glutamate in addition to those present in normal rat hepatocytes. 946 18

Previous studies in this laboratory revealed that nitric oxide (NO) reversibly inhibits the respiration of isolated mitochondria and ascites hepatoma (AH-130) cells by an oxygen concentration-dependent mechanism. The inhibitory effect of NO on the respiration of AH-130 cells was enhanced by treating with digitonin that selectively permeabilized plasma membranes and released cytosolic low-molecular-weight compounds. Reduced glutathione (GSH) is the most abundant cytosolic thiol that easily reacts with NO. To elucidate the mechanism by which digitonin enhanced the inhibitory action of NO, the effect of GSH and related thiols was studied with AH-130 cells and their mitochondria. The inhibitory effect of NO on the respiration of digitonin-treated cells was suppressed by either GSH, L-cysteine, or N-acetylcysteine, but not by oxidized glutathione. The inhibitory effect of NO on the respiration of their mitochondria was also decreased by GSH. In contrast, the inhibitory effect of NO was markedly enhanced with AH-130 cells obtained from animals that were pretreated with L-buthionine sulfoximine (BSO), a specific inhibitor for GSH synthesis. Kinetic analysis revealed that NO dose-dependently decreased GSH levels in AH-130 cells with concomitant generation of S-nitrosothiols. Although S-nitrosoglutathione (GSNO), a slow releaser of NO, also inhibited the respiration of tumor cell mitochondria, its effect was significantly lower than that of NO. These results suggest that cellular GSH might play pivotal roles in the regulation of energy metabolism in hepatoma cells by modulating free forms of NO.
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PMID:Role of glutathione in nitric oxide-dependent regulation of energy metabolism in rat hepatoma cells. 946 40

Previously we observed that the finger/growth factor (FG) region of tissue-type plasminogen activator (t-PA) blocked the low-density-lipoprotein-receptor-related protein (LRP)-mediated clearance of t-PA by rat hepatocytes. However, the concentrations needed were much higher than those for intact t-PA. The FG region was expressed in yeast and lacked the fucose on Thr61, which was reported to be important for efficient clearance of t-PA by human hepatoma cells. At position 83 it had a serine, whereas human t-PA has a free cysteine and rodent t-PA an arginine at this position. To understand the reason for the low efficacy of the FG protein we produced in CHO cells chimeric molecules composed of two FG modules linked to the Fc portion of human IgG1 (FG2-Fc). Two variants were studied, one having Ser83, the other Arg83. The two fucosylated FG2-Fc chimeras were compared with each other, with non-fucosylated FG and with intact t-PA with regard to their effect on the clearance of t-PA and t-PA x plasminogen-activator inhibitor type 1 (PAI-1). For this comparison, LRP-specific clearance models were used. In rat hepatoma cells and in mouse embryonic fibroblasts (MEF-1) the clearance of t-PA and of t-PA x PAI-1 was inhibited more than 95% by receptor-associated protein, an inhibitor of LRP-mediated clearance, whereas no t-PA or t-PA x PAI-1 clearance was observed in LRP-deficient PEA-13 mouse embryonic fibroblasts. The Ser83 and Arg83 FG2-Fc chimeras were equally efficient inhibitors in these models. Their efficacies in inhibiting t-PA and t-PA x PAI-1 degradation (IC50 750 nM and 890 nM, respectively) were similar to those of non-fucosylated FG (IC50 1950 nM and 1560 nM) and 75-fold lower than that of intact t-PA (IC50 9.9 nM and 21.1 nM). The results indicate that the presence of a serine or an arginine at position 83 and the presence of a fucose on Thr61 are not of major importance for the LRP-mediated clearance of t-PA.
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PMID:Studies on the effect of fucosylated and non-fucosylated finger/growth-factor constructs on the clearance of tissue-type plasminogen activator mediated by the low-density-lipoprotein-receptor-related protein. 949 55

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