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)

Two lines of evidence led us to reexamine the possibility that methylation of phosphoethanolamine and its partially methylated derivatives, in addition to methylation of the corresponding phosphatidyl derivatives, plays a role in mammalian phosphatidylcholine biosynthesis: (a) Results obtained by Salerno and Beeler with rat [Salerno, D.M. and Beeler, D.A. (1973) Biochim. Biophys. Acta 326, 325-338] appear to strongly support such a role for methylation of phosphobases; (b) Such reactions have recently been shown to play major roles in phosphatidylcholine synthesis by higher plants [see Datko, A.H. and Mudd, S.H. (1988) Plant Physiol. 88, 854-861 and references therein]. We found that, following continuous labeling of rat liver with L-[methyl-3H]methionine for 10.4 min (intraperitoneal administration) or for 0.75 min (intraportal administration), virtually no 3H was detected in methylated derivatives of phosphoethanolamine, but readily detectable amounts of 3H were present in the base moiety of each methylated derivative of phosphatidylethanolamine. Thus, there was no indication that phospho-base methylation makes a significant contribution. Studies of cultured rat hepatoma cells showed definitively for the first time in a mammalian system that choline deprivation up-regulates the rate of flow of methyl groups originating in methionine into phosphatidylethanolamine and derivatives. Even under these conditions, methylation of phosphoethanolamine bases appeared to play a negligible role.
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PMID:Phosphatidylcholine synthesis in the rat: the substrate for methylation and regulation by choline. 233 15

The effects of selenomethionine (SeMet) on the growth of 17 cultured cell lines were studied. SeMet in the culture medium of three hepatoma cell lines promoted cell growth at subcytotoxic levels (1-20 microM), but the growth of malignant lymphoid and myeloid cells was not stimulated. L-SeMet was cytotoxic to all 17 cell lines when assayed after culture for 3-10 days. A 50% growth inhibition was observed by 30-160 microM-SeMet in a culture medium containing 100 microM-methionine. SeMet cytotoxicity to normal (fibroblasts) and malignant cells was rather similar, excluding specific antineoplastic cytotoxicity. Cytotoxicity was increased by decreasing concentrations of methionine. The DL form of SeMet was less cytotoxic than the L form. L-SeMet was metabolized to a selenium analogue of S-adenosylmethionine approximately as effectively as the natural sulphur analogue methionine in malignant R1.1 lymphoblasts. Concomitantly, S-adenosylmethionine pools were decreased. This occurred early and at cytotoxic SeMet levels. Methionine adenosyltransferase activity was not altered by SeMet treatment. ATP pools were not affected early, and decreases in the synthesis of DNA and protein took place late and were apparently related to cell death. RNA synthesis was slightly stimulated at low cytotoxic SeMet levels by 24 h, but was markedly inhibited after 48 h. The SeMet analogue of S-adenosylmethionine could be effectively utilized in a specific enzymic transmethylation. Neither S-adenosylhomocysteine nor its selenium analogue accumulated in the treated cells. These findings together suggest a direct or indirect involvement of S-adenosylmethionine metabolism in SeMet cytotoxicity, but exclude a gross blockage of transmethylations.
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PMID:Effects of selenomethionine on cell growth and on S-adenosylmethionine metabolism in cultured malignant cells. 233 86

The effects of concurrent addition of methionine (Met) and glycine (Gly) to a 20% casein diet on serum lipoprotein profiles and fecal sterol excretion were studied in male Donryu rats with or without subcutaneous implantation of an ascites hepatoma line of AH109A cells. The hepatoma-bearing rats fed on the 20% casein diet had a notable elevation in the very-low-density lipoprotein + low-density lipoprotein (VLDL + LDL)-cholesterol (Ch) level with a slight but significant decrease in high-density lipoprotein (HDL)-Ch level when compared to the hepatoma-free (normal) rats fed on the same diet. The dietary addition of 1.2% Met and 2.5% Gly in combination suppressed the hepatoma-induced elevation in the (VLDL + LDL)-Ch level with a prevention of the hepatoma-induced decrease in the HDL-Ch level. The addition of the two amino acids also lowered significantly the (VLDL + LDL)-Ch level without affecting the HDL-Ch level in tumor-free rats. Fecal excretion of both neutral and acidic sterols were reduced with growth of the hepatoma. The dietary addition of Met and Gly exerted no or little influence on neutral sterol excretion in both the tumor-free and -bearing states, but it enhanced acidic sterol excretion into feces in both states, especially in the hepatoma-bearing state at the last stage of feeding. These results suggest that the excretion and catabolism of Ch might be impaired in hepatoma-bearing rats with growth of the tumor, and that the supplemental Met and Gly in combination might enhance Ch catabolism by stimulating either synthesis or conjugation of bile acids, leading to a reduction of the (VLDL + LDL)-Ch level in the normal and hepatoma-bearing states.
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PMID:Effects of dietary methionine and glycine on serum lipoprotein profiles and fecal sterol excretion in normal and hepatoma-bearing rats. 236 24

Betaine-homocysteine- and S-adenosylmethionine-homocysteine-methyltransferases which catalyze synthesis of methionine from homocysteine are absent in tumor cells such as mouse Ehrlich ascites tumor cells and rat hepatoma AH-109A ascites cells.
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PMID:Deficiency of methionine synthesis enzyme activity in ascites tumor cells. 236 13

The ability of the dietary methyl donors methionine and choline to inhibit the carcinogenic and tumor-promoting effects of phenobarbital (PB) in the livers of male weanling C3H mice was examined. The mice were fed a commercial rodent diet with or without 0.05% PB. Thirty animals from each set received the diet with either: (1) no dietary supplementation, (2) an additional 1.0% choline chloride, (3) 1.5% DL-methionine or (4) both 1.5% DL-methionine and 1.0% choline chloride. Additional groups of 30 animals with the same eight dietary and PB-treatment regimens described above were given a single initiating dose of 150 mg diethylnitrosamine (DENA)/kg body wt dissolved in saline, or the saline solution only, 1 week prior to the start of PB feeding. The 16 treatment groups were fed their respective diets for 12 months. Statistical trend analysis showed that increasing levels of supplemental methyl donors gave highly significant protection in PB-treated mice (P less than 0.01). The incidence of liver carcinomas in the four dietary groups not receiving PB or DENA varied from 0 to 7%. The PB-treated animals not receiving an initiating dose of DENA developed hepatocellular carcinomas (HCCs) at incidences of 79% in group 1 animals, 74% in group 2 animals, 60% in group 3 animals, and 31% in group 2 animals respectively. Thus, incidence of HCCs in group 4 was significantly lower than in groups 1, 2 or 3 (P less than 0.01). However, the total incidence of liver tumors (adenomas plus carcinomas) was about the same in all DENA or PB-treated groups. Thus, dietary supplementation with methyl donors increased the proportion of animals bearing liver adenomas as their most advanced hepatic lesion in PB-treated mice. In DENA-treated mice fed PB, dietary supplementation with methionine and choline protected against the formation of liver carcinomas (P less than 0.02); however, methionine and choline had no significant effect on liver tumor formation in mice fed the PB-free diets. Methionine and choline supplementation gave significant protection against HCC metastases in the lungs of the tumor-bearing mice in groups initiated with DENA followed by PB promotion. These results support the hypothesis that PB exerts it tumorigenic activity in mice at least in part through a physiological insufficiency of labile methyl groups.
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PMID:The inhibition by methionine and choline of liver carcinoma formation in male C3H mice dosed with diethylnitrosamine and fed phenobarbital. 238 15

The regulation of succinyl-CoA:acetoacetyl-CoA transferase (CoA transferase) has been studied in 8 rat hepatoma cell lines. Compared with normal rat hepatocytes, which have almost nondetectable activity of the enzyme, the hepatoma cell lines have a wide range of expression of CoA transferase activity, from as low as 45 nmol/min/mg to as high as 960 nmol/min/mg. Western blotting showed that the different levels of CoA transferase activity were due to differing amounts of the enzyme in the cells. This was further attributed to the varying amounts of the enzyme synthesized in the cells as monitored by L-[35S]methionine labeling followed by immunoprecipitation. To study further the differential expression of CoA transferase in the hepatoma cell lines, the relative quantity of functional CoA-transferase mRNA in the cells was measured by in vitro translation. The results showed that the levels of functional CoA transferase mRNA detected were consistent with the differences in the enzyme activity in the cells. Since CoA transferase is the key enzyme responsible for the utilization of ketone bodies as an alternative energy source, the expression of CoA transferase in hepatoma cells may play a role in energy production.
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PMID:Regulation of succinyl coenzyme A:acetoacetyl coenzyme A transferase in rat hepatoma cell lines. 239 55

The assembly of mitochondrially and cytoplasmically translated subunits of NADH dehydrogenase in the inner mitochondrial membrane was studied in rat hepatoma cultures. A polyclonal antibody to the purified bovine heart holoenzyme, which reacted with comigrating proteins of both rat liver and hepatoma mitochondria on immunoblots, precipitated 25-30 [35S]methionine-labeled proteins from hepatoma cell lysates. Six of these were sensitive to an inhibitor of mitochondrial translation (chloramphenicol), resistant to an inhibitor of cytosolic translation (cycloheximide), and were not present in cytochrome oxidase. By these criteria, six NADH dehydrogenase subunits are identified as being translated on mitochondrial ribosomes. The metabolic properties of the three most prominent of these at 51, 43, and 11 kDa were studied in more detail. Mitochondrial and nuclear-coded polypeptides assemble into NADH dehydrogenase at different rates as measured by incorporation of pulse-labeled proteins into immunoprecipitable enzyme. Nuclear-coded, imported polypeptides appear immediately after a pulse with [35S]methionine and retain constant stoichiometry. Mitochondrially coded proteins, although rapidly translated, appear at peak levels at different times between 0 and 12 h of chase in the immunoprecipitated enzyme. Ongoing synthesis and import of nuclear-coded proteins is necessary for mitochondrially coded proteins to be assembled. Excess, unassembled mitochondrially translated subunits are degraded in an oligomycin-sensitive manner. These data are consistent with a model in which a scaffold of imported proteins forms the inner core of the enzyme, and later arriving mitochondrially translated proteins attach to the scaffold in a time-dependent manner.
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PMID:Respiratory chain-linked NADH dehydrogenase. Mechanisms of assembly. 239 60

A new scleroderma antigen of Mr = 34,000; pI, 8.5 has been identified. This 34-kDa protein is a nucleolar protein as determined by immunostaining procedures with affinity-purified antibodies. The 34-kDa protein was shown to localize to the fibrillar regions of the nucleolus by immunoelectron microscopy. Antibodies against the 34-kDa protein precipitate U3 RNA-containing particles. The 34-kDa protein has been isolated from Novikoff hepatoma cell nucleoli by ion exchange and reverse-phase column chromatography. The protein contains 4.1 mol % NG,NG-dimethylarginine (DMA) and 22.8 mol % glycine. It is the most highly arginine-methylated protein thus far detected in higher eukaryotes. This nucleolar 34-kDa protein resembles several nucleoplasmic proteins that are associated with heterogeneous nuclear RNA with respect to isoelectric point, Mr, presence of NG,NG-dimethylarginine, and its high glycine content. The amino-terminal sequence of the first 31 residues of the 34-kDa protein is: Met-Lys-Pro-Gly-Phe-Ser-Pro-DMA-Gly-Gly-Gly-Phe-Gly-Gly-DMA-Gly-Gly- Phe-Gly-Asp-DMA-Gly-Gly-DMA-Gly-Gly-Gly-DMA-Gly-Gly-DMA. In the first 31 residues, there are 16 glycine, 6 DMA, and 3 phenylalanine residues. This is a novel demonstration of clusters of glycine and DMA in a protein.
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PMID:Purification and partial characterization of a nucleolar scleroderma antigen (Mr = 34,000; pI, 8.5) rich in NG,NG-dimethylarginine. 241 94

The variant cell line of H4-II-E-C3 cells derived from the Reuber H-35 hepatoma cells has been established using protein- and lipid-free synthetic medium. This H4-II-E-C3-V line can synthesize and secrete considerable amounts of alpha-fetoprotein (AFP) and albumin. The addition of 5 X 10(-7) M dexamethasone to the medium stimulated the excretion of AFP without increasing total AFP synthesis, whereas 8.7 X 10(-8) M insulin inhibited the excretion of AFP without a significant inhibition of intracellular AFP synthesis. However, neither dexamethasone nor insulin altered either the cellular or secreted levels of albumin. Cells were pulse labeled with [35S]methionine and then chased after addition of excess unlabeled methionine. AFP appeared in the medium after 10 min, and 50% of the protein was secreted after 110 min. The rate of secretion of AFP was much slower than that of albumin, 50% of which was secreted after 25 min. Dexamethasone, 5 X 10(-7) M, caused a marked enhancement in the rate of AFP secretion, with 50% released after 75 min. Insulin, 8.7 X 10(-8) M, by contrast, caused a marked delay in AFP secretion with only 20% released after 180 min and then a plateau was approached. Since the intracellular AFP was excreted 55% after 180 min the remaining 25% of newly made AFP was suggested to be degraded during secretion. The kinetics of movement of AFP during secretion and endoglycosidase H treatment of intracellular and secreted AFP suggested that insulin impeded the transport of AFP from the rough endoplasmic reticulum to the Golgi apparatus.
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PMID:Hormonal regulation during secretion of alpha-fetoprotein in hepatoma cells grown in synthetic medium. 241 28

Previous studies in this laboratory suggested that in adult liver, either the gene for the tumor-type poly(A) polymerase is poorly transcribed or the mRNA for this enzyme is largely not expressed. To test these possibilities, total RNA from rat liver and Morris hepatoma 3924A RNA were isolated by using a guanidine thiocyanate method; poly(A+) RNA and poly(A-) RNA were separated by oligo(dT)-cellulose chromatography and used for translation in a rabbit reticulocyte lysate system. After in vitro translation, the products were immunoprecipitated with either purified anti-tumor poly(A) polymerase antibodies or control immunoglobulins. When the polypeptides translated from poly(A+) or poly(A-) hepatoma RNA were precipitated with immune sera, a unique [35S]methionine-labeled 35-kilodalton (kDa) protein was observed. This band was not apparent when control serum was used for the immunoprecipitation. The radiolabeled 35-kDa polypeptide was not evident when the products were incubated with highly purified tumor nuclear poly(A) polymerase prior to immunoprecipitation. Prior incubation of the translation products with bovine serum albumin instead of poly(A) polymerase had no effect on the immunoprecipitation. This 35-kDa protein was not apparent when liver poly(A+) RNA was used to direct translation. These data demonstrate that (a) the tumor enzyme is not synthesized as a precursor, (b) tumor mRNA, but not normal liver mRNA, contains detectable sequences coding for tumor-type poly(A) polymerase, and (c) poly(A) polymerase mRNA also exists as a poly(A-) population.
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PMID:Cell-free synthesis of tumor-type poly(A) polymerase. 242 13


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