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)

To develop a model for studies of liver growth control, we characterized cell cycle synchronization of liver-derived cells with sodium butyrate. Exposure of cultured HTC (rat hepatoma) cells to 5 mM butyrate arrested cell growth in a reversible manner. Flow cytometric analysis revealed that butyrate-treated HTC cells were restricted in G0/G1, as well as S/G2M phases. After release from butyrate arrest, HTC cells underwent synchronous cycles of DNA synthesis and transited through S phase. Inhibition of cell growth by butyrate was associated with a complex pattern of cell cycle regulated gene expression, including a decoupling of c-fos and c-jun gene expression. Transcription of c-fos, as well as c-jun increased with butyrate arrest, whereas steady rate mRNA levels of c-jun only were increased, suggesting additional regulation of c-fos. In addition, butyrate-arrested cells exhibited a transcriptionally determined accumulation of H3 histone, C-Ha-ras and ornithine decarboxylase mRNAs, suggesting that cell cycle-related check points following the onset of S phase were modulated. An increase in c-myc mRNA levels in butyrate-arrested cells was post-transcriptionally regulated. After release from butyrate-arrest, the abundance of immediate early, as well as S phase regulated, gene expression changed coordinately with S phase cell transitions. Thus, exposure of HTC cells to butyrate modulates cell cycle regulated gene expression, inhibits cycling, and results in accumulation of cells in specific compartments. Synchronization of liver cells with butyrate should, therefore, provide a useful model for defining cell cycle-related events in response to various mitogenic stimuli.
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PMID:Butyrate synchronization of hepatocytes: modulation of cycling and cell cycle regulated gene expression. 794 6

The expression of the two proto-oncogenes ornithine decarboxylase and c-met was examined during various phases of growth of Yoshida AH-130 ascites hepatoma. Ornithine decarboxylase (ODC) and c-met mRNA levels declined progressively from day 5 (exponential growth-phase) until day 14 (quasi-stationary growth-phase). Transcription rate for both the genes remained constant between days 5 and 10, while decreasing at day 14. ODC activity was consistent with ODC mRNA level during hepatoma growth. In host liver, ODC mRNA accumulated 5 and 14 days after tumor transplantation, while c-met mRNA level was elevated until day 10 and diminished at day 14. ODC activity triplicated at day 14 in host liver. The progressive decline in the expression of ODC and c-met observed in hepatoma might be one of the mechanisms important for the control of tumor growth.
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PMID:Expression patterns of ornithine decarboxylase and c-met in growing Yoshida AH-130 hepatoma. 795 67

DH23A cells, an alpha-difluoromethylornithine (DFMO)-resistant variant of rat hepatoma tissue culture cells (HTC), contain high levels of very stable ornithine decarboxylase (ODC). In the absence of DFMO, the high ODC activity results in a large accumulation of endogenous putrescine. Concomitant with the putrescine increase is a period of cytostasis and a subsequent loss of viable cells. In contrast, HTC cells with a moderate polyamine content can be maintained in exponential growth. This suggests that a moderate polyamine concentration is necessary for both optimal cell growth and survival. The cytotoxicity observed in the DH23A cells is apparently not due to byproducts of polyamine oxidation or alterations in steady state intracellular pH or free [Ca2+]. It is possible to mimic the effects of high levels of stable ODC by treatment of cells with exogenous putrescine in the presence of DFMO. This suggests that overaccumulation of putrescine is the causative agent in the observed cytotoxicity, although the mechanism is unclear. These data support the hypothesis that downregulation of ODC may be necessary to prevent accumulation of cytotoxic concentrations of the polyamines.
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PMID:Consequences of aberrant ornithine decarboxylase regulation in rat hepatoma cells. 810 60

Macrophage-like RAW 264 and H35 hepatoma cells grown under serum-free conditions exported putrescine and an unidentified diamine into the culture medium. Unlike putrescine, the unknown compound could be detected only extracellularly. Analyses of dansylated polyamine standards and mass spectroscopy confirmed that the unknown compound was cadaverine (1,5-diaminopentane). The cells were free of mycoplasma as evidenced by a negative result using a probe specific for prokaryotic rRNA. After prophylactic treatments with two different mycoplasmacidal agents, the cells continued to export cadaverine. Attempts to "infect" a noncadaverine-exporting cell line with culture medium and cell-free lysates proved unsuccessful, establishing that cadaverine was in fact a bona fide product of these mammalian cells. Cadaverine export by RAW 264 and H35 cells was stimulated by lipopolysaccharide and insulin, respectively. However, administration of exogenous ornithine caused cadaverine export to decrease significantly with concomitant increases in putrescine export. alpha-Difluoromethylornithine, a selective inhibitor of ornithine decarboxylase, inhibited both cadaverine and putrescine export. When cells were labeled with [3H]lysine, the great majority of the radioactivity recovered in exported polyamines was found in cadaverine. The cumulative data suggested that cadaverine formation may be caused by the action of intracellular ornithine decarboxylase upon lysine to produce cadaverine, which is then effluxed from the cell with a high degree of efficiency.
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PMID:Biosynthesis and selective export of 1,5-diaminopentane (cadaverine) in mycoplasma-free cultured mammalian cells. 812 59

Cultured Reuber H35 rat hepatoma cells under highly viable serum-free conditions were found to selectively export putrescine from inside the cell into the culture medium, but not spermidine, spermine, or their acetylated derivatives. Even untreated cells, with very low intracellular putrescine levels, constitutively exported significant amounts of only putrescine for a 12 h period. Administration of the phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate) which markedly elevates ornithine decarboxylase (ODC), did not potentiate putrescine export over what was measured in the unstimulated cultures. However, addition of 1 mM ornithine to the cultures resulted in increased intracellular putrescine (maximum at 4 h) with a marked concomitant increase in putrescine export between 0 and 8 h, after which putrescine export again stopped. Treatment with 10(-7) M insulin yielded intracellular putrescine levels that remained elevated for 36 along with a continuous and more rapid export of putrescine over the same 36 h time period. When insulin and ornithine were administered together, even higher levels of intracellular putrescine and putrescine export were observed, with putrescine efflux proceeding over the 36 h time-course at the highest observed rates of 1.5 (0-12 h) and 1.0 (12-36 h) nmol/mg total protein per h. Exposure to DFMO, an inhibitor of ODC, depleted intracellular putrescine stores and effectively suppressed putrescine export. There was not a positive correlation between the time-dependent decreases in the intracellular putrescine concentrations and the respective alterations in the rate of putrescine export under a variety of conditions. Furthermore, the drug verapamil was capable of completely inhibiting putrescine export (IC50 approx. 1 microM) without any change in the level of intracellular putrescine. This data was not consistent with the involvement of simple diffusion of putrescine through the membrane as the major mechanism for putrescine export. The potential mechanisms involved in putrescine export and the role of this process in regulating intracellular polyamine levels, as well as, possible functions of extracellular putrescine are discussed.
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PMID:Selective putrescine export is regulated by insulin and ornithine in Reuber H35 hepatoma cells. 818 61

Ornithine decarboxylase (ODC) degradation in a freshly prepared reticulocyte lysate was examined. Immunodepletion of proteasomes from the reticulocyte lysate resulted in almost complete loss of ODC degradation. In contrast with the previously reported degradation in extracts of hepatoma tissue-culture (HTC) and Chinese-hamster ovary (CHO) cells or that by the purified 26 S proteasome, efficient degradation of ODC was observed in the lysate without exogenous antizyme, an ODC protein inhibitor induced by polyamines, owing to the presence of a significant amount of antizyme in the lysate. The degradation of ODC in the lysate was strongly suppressed on inactivation of antizyme in the lysate with antizyme inhibitor, a protein which binds to the antizyme and releases ODC from the ODC-antizyme complex. Thus the main pathway for ODC degradation in a reticulocyte lysate was essentially the same as that characterized previously in extracts of HTC and CHO cells, namely an ATP- and antizyme-dependent 26 S proteasome-catalysed pathway that is presumed to be responsible for ODC degradation in whole cells.
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PMID:Involvement of the proteasome and antizyme in ornithine decarboxylase degradation by a reticulocyte lysate. 821 32

New retinoids have been synthesized and screened in the search for chemopreventive agents of cancer. N-4-(Carboxyphenyl) retinamide showed a significant inhibitiory effect on carcinogenesis of cancers in the buccal pouch of hamsters and in the forestomach of mice. Clinical studies have demonstrated that N-4-(carboxyphenyl) retinamide is effective against oral leukoplakia, vulvar leukoplakia, and dysplasia of the uterine cervix and stomach. Field studies among a population at high risk for esophageal cancer in Linxian County, Henan Province, revealed that N-4-(ethoxycarbophenyl) retinamide decreased the incidence of this cancer. Qidong County is a high-risk area for hepatoma in China. This has been correlated to the low levels of selenium in the blood of the residents as well as in grain grown in the area. S. Y. Yu, W. G. Li, Y. J. Zhu, et al. (Biol. Trace Element Res. 1985; 7:22-26) reported that the administration of selenium inhibited the incidence of hepatoma induced by aflatoxin B in rats and in ducks. Experimental studies demonstrated that green tea extract inhibited 12-O-tetradecanoylphorbol-3-acetate-induced epidermal ornithine decarboxylase activity and counteracted 12-O-tetradecanoylphorbol-3-acetate-induced ear edema in mice. It is interesting that green tea extract inhibited the transformation of Balb/c 3T3 cells induced by methylcholanthrene and 12-O-tetradenanoylphorbol-3-acetate. Garlic has been used for thousands of years in Chinese cooking and folk medicine. Epidemiological studies show that the dietary intake of garlic is inversely related to gastric cancer incidence in Shandong Province.
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PMID:Highlights of the cancer chemoprevention studies in China. 823 11

The half-life of ornithine decarboxylase (ODC) in HMOA cells, a variant cell line derived from hepatoma tissue culture (HTC) cells, is markedly increased compared with that in the parental cell line. In the present study, we examined which of the three relevant factors is responsible for the ODC stabilization in HMOA cells, namely ODC itself, a regulatory protein antizyme and an ODC-degrading activity. SDS/PAGE analysis of radiolabeled ODC revealed that ODC from HMOA cells migrated somewhat faster than that from HTC cells, suggesting that HMOA ODC was structurally altered. Direct sequencing of reverse-transcription/polymerase-chain-reaction (RT-PCR) products of ODC mRNA from HMOA cells revealed a T to G replacement, causing a Cys441-->Trp replacement near the C-terminus. No alteration was found in the whole coding region of antizyme mRNA. An authentic mutant ODC cDNA with the same replacement was transfected and expressed in C55.7 ODC-deficient Chinese hamster ovary cells. Upon cycloheximide treatment, the mutant ODC activity did not decrease appreciably for at least 3 h, whereas wild-type ODC activity decreased with a half-life of 1 h. In-vitro-synthesized mutant ODC with the Cys441-->Trp (or Ala) replacement was also stable in a reticulocyte-lysate ODC-degradation system. Metabolically labeled and purified mouse ODC was degraded in HMOA cell extracts in the presence of ATP and antizyme as rapidly as in HTC cell extracts, indicating that HMOA cells have a normal ODC degrading activity. These results indicated that the single amino acid replacement, Cys441-->Trp, is responsible for the stabilization of ODC in HMOA cells and that Cys441 is important for rapid ODC turnover.
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PMID:Single amino-acid replacement is responsible for the stabilization of ornithine decarboxylase in HMOA cells. 831 92

There is indirect evidence that key enzymes which catalyse both synthesis and degradation of polyamines (PA) may be useful as biological markers of malignant growth. Ornithine decarboxylase (ODC) activity was assessed in fetal, regenerating and adult rat liver, in hepatoma with different growth rate, in Morris hepatoma cell lines and in rat liver in the course of nitrosopiperidine (NP) carcinogenesis. A much higher ODC activity was observed in all the investigated tumor tissues and in regenerating rat liver as well. A significant decrease of ODC inductive synthesis was demonstrated both in liver and hepatoma of rats maintained on vitamin B6-deficient diet. The experimental suggest that inductive synthesis of ODC may be considered not only early, but also the mandatory event in any hyperproliferating processes including carcinogenesis.
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PMID:[Ornithine decarboxylase and malignant growth]. 837 36

During growth stimulation of cells, Ca2+ and amino acids of the A, ASC and N transport systems are important for the induction of ornithine decarboxylase (ODC, L-ornithine carboxylase, EC 4.1.1.17). In order to clarify the relationship between Ca2+ and amino acids, we studied the induction of ODC by asparagine under three different Ca2+ states in H-35 rat hepatoma cells. First, in normal cells, extracellular Ca2+ above 0.1 mM and 10 mM asparagine separately stimulated ODC activity and their effects were approximately additive. In these normal cells, asparagine could act in the absence of medium Ca2+. TMB-8, a sequestered-Ca2+ release antagonist, had no effect on ODC induction whilst the asparagine action is sensitive to treatment with W7, a Ca-calmodulin antagonist, or lanthanum, a Ca2+ antagonist. Secondly, in cells treated with 0.5 mM EGTA in Ca(2+)-free medium, the asparagine action on ODC induction was blocked but the inhibition could be reversed by the addition of Ca2+ to the medium. Thirdly, ionomycin treatment in the absence of medium Ca2+ did not block the asparagine effect. Furthermore, in ionomycin-treated cells, the presence of high levels of medium Ca2+ increased ODC activity, but this increase was additive to, and could not replace, the action of asparagine. Our results indicate that the asparagine action does not depend on an increase of intracellular free-Ca2+.
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PMID:Independent actions of asparagine and high levels of free Ca2+ in the induction of ornithine decarboxylase. 843 91


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