Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.1.1.32 (phosphoenolpyruvate carboxykinase)
 4,204 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activities of pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and glycogen synthetase (GS) were determined in the cancerous and in the apparently uninvolved (host) regions of livers from primary hepatoma patients as well as in normal adult human livers and human fetal livers. The activities of these enzymes were also assayed in a fairly fast-growing, 3'-methyl-4-dimethylaminoazobenzene-induced transplantable rat hepatoma and in hepatoma cell lines derived from both rat and human tumors. In the human hepatoma, as in the rat hepatoma, the activities of PC, PEPCK, and G6Pase were considerably reduced, compared to those in the host liver. The activities of both the a (glucose 6-phosphate-independent) and b (glucose 6-phosphate-dependent) forms of GS were also lower in human and rat hepatomas than in the respective host livers. Activities of PC, PEPCK, and G6Pase in the human hepatomas were often comparable with those of fetal livers. In rat and human hepatoma cells, the activities of PC, PEPCK, and G6Pase were similar to or lower than the activities in the respective hepatomas; the activities of GS a were also similar to those in the hepatoma, whereas the activities of GS b were somewhat higher.
Cancer Res 1978 May
PMID:Activities of key gluconeogenic enzymes and glycogen synthase in rat and human livers, hepatomas, and hepatoma cell cultures. 20 62

Patients manifesting the syndrome of cachexia of malignancy exhibit an abnormal diabetic glucose tolerance. In our patients this has been correlated with a marked resistance to administered insulin, while insulin receptors on monocytes are normal. Lipolysis remains responsive to the effects of insulin. The oxidation of FFA, as a substrate for metabolism, has been reported to be increased, and the utilization of glucose as a metabolic fuel is reduced. Increased Cori cycle activity has been demonstrated, which produces an enhanced gluconeogenesis from lactate and amino acids; there is an expenditure of 6 ATP for the synthesis of each mole of glucose. An attempt to interrupt the Cori cycle in man, using hydrazine sulfate to inhibit the enzyme phosphoenolpyruvate carboxykinase, has not resulted in reproducible clinical benefit. However, successful treatment of the underlying tumor may produce a total reversal of the cachexia syndrome, suggesting that neoplasms have the potential to elaborate an, as yet, unidentified metabolic toxin. The use of insulin to counteract the reported abnormalities should be examined as a possible supportive measure in the total nutritional management of the cancer patient.
Cancer 1979 May
PMID:Cachexia of malignancy: potential role of insulin in nutritional management. 44 87

Transgenic animals expressing genes capable of repairing DNA may be a valuable tool to study the effect of DNA-damaging agents on tissue-specific carcinogenesis. For this reason, we constructed a chimeric gene consisting of the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) gene linked to the Escherichia coli ada gene coding for O6-alkylguanine-DNA alkyltransferase and the polyadenylate region from the bovine growth hormone gene. The PEPCK promoter results in gene expression in liver and kidney and is induced by hormones, and its transcription is regulated by diet. The chimeric PEPCK ada gene was injected into the male pronucleus of fertilized eggs to produce transgenic mice. Six of 65 developing mice contained 5-10 copies of the intact trans gene per genome. Two founders transmitted the trans gene in a heterozygous manner, whereas 3 transmitted as germ line mosaics and 1 did not transmit to F1 offspring. All F1 offspring carrying the PEPCK ada trans gene expressed ada mRNA in liver and kidney and produced a functional alkyltransferase with a protein molecular weight of 39,000 originating from the bacterial gene. Total alkyltransferase activity was increased in the liver of F1 offspring from all founder mice, but offspring of only one founder had elevated renal alkyltransferase levels. A diet high in protein markedly increased ada mRNA and alkyltransferase activity within 1 week in both liver and kidney, whereas a high carbohydrate diet for 1 week markedly reduced expression of PEPCK ada and alkyltransferase levels. Nontransgenic animals were unaffected by these dietary manipulations. During induction with a high protein diet, hepatic alkyltransferase in transgenic mice was 16.6 +/- 1.5 units/micrograms DNA (mean +/- SE) compared to 5.3 +/- 0.6 units/micrograms DNA in control animals. This level of alkyltransferase is higher than that in any mammalian tissue noted previously except human liver. Transgenic animals expressing high levels of alkyltransferase should help define the role of DNA repair in protection from carcinogenesis induced by N-nitroso compounds.
Cancer Res 1990 Mar 15
PMID:High level, regulated expression of the chimeric P-enolpyruvate carboxykinase (GTP)-bacterial O6-alkylguanine-DNA alkyltransferase (ada) gene in transgenic mice. 240 42

Although the precise mechanism of endotoxin lethality has yet to be defined, it is well recognized that the amount of hepatic phosphoenolpyruvate carboxykinase is reproducibly and significantly reduced after challenge with endotoxin. Hydrazine has been shown to be a specific inhibitor of gluconeogenesis, causing a metabolic crossover at the step catalyzed by phosphoenolpyruvate carboxykinase. More recently, it has also been shown that hydrazine sulfate may be of potential therapeutic value against cancer cachexia. The experiments described in this paper demonstrate that treatment of CF1 mice with hydrazine sulfate 5 h prior to challenge with endotoxin from Salmonella enteritidis significantly improved survival. Furthermore, such treatment counteracted the drop in hepatic phosphoenolpyruvate carboxykinase activity in isolated cytosol otherwise evident at 6 h and 12 h after endotoxin challenge. Despite this, there was no corresponding improvement in the plasma glucose, measured at 6, 12, and 24 h following endotoxin challenge. It is suggested that the endogenous response to the metabolic crossover initiated by hydrazine may contribute to the protection. The response to hydrazine sulfate has yet to be fully elaborated but does include the increase in phosphoenolpyruvate carboxykinase activity. In contrast with the protection seen upon hydrazine sulfate pretreatment, injecting a corresponding dose of hydrazine sulfate after the endotoxin resulted in more fatalities.
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PMID:Modulation of endotoxin lethality in mice by hydrazine sulfate. 273 84

The accelerated mobilization of peripheral protein and subsequent increased gluconeogenesis are regarded as mechanisms of cancer cachexia. To determine the relation of gluconeogenesis to different degrees of tumor burden and subsequent tumor removal in the fed and fasted states, we examined the activity and mRNA levels of the key regulatory enzyme for gluconeogenesis: phosphoenolpyruvate carboxykinase (PEPck) in the liver of Fischer rats with a transplanted methylcholanthrene-induced sarcoma. PEPck activity in liver cytosol, after a 24-hour fast, was significantly higher in the tumor-bearing rats than in their pair-fed controls. The increase in enzyme activity was clearly evident at 8% tumor burden and correlated positively with the degree of tumor burden (r = 0.85, p less than 0.01). Removal of the tumor produced a complete reversal of PEPck activity 10 days after excision. Regular feeding also abolished this increased enzyme activity. A similar trend was seen in the mitochondria. PEPck mRNA levels of rats with greater than 11% tumor burden in the fed state were decreased more than those of controls. PEPck mRNA levels were equally elevated in tumor bearers and controls in the 24-hour-fasted state. These results suggest that tumor-bearing simulates the fasted state associated with hypoglycemia, which in turn triggers induction of the gluconeogenic enzyme, PEPck.
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PMID:The reversal of increased gluconeogenesis in the tumor-bearing rat by tumor removal and food intake. 276 39

Severe weight loss is associated with many malignant diseases of humans and animals. Avian reticuloendotheliosis viruses (RE viruses) induce runting in experimentally infected chickens. Chickens infected with a replication-competent RE virus, reticuloendotheliosis-associated virus, weighed 30-50% less than control birds at the time of death. Chickens infected with reticuloendotheliosis virus, a replication-defective acute leukemia virus, weighed 30% less than the controls. The runting induced by RE viruses does not occur because of reduced food intake. Activities of phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme in the liver, were reduced approximately 40 and 50%, respectively, by infection with reticuloendotheliosis-associated virus and reticuloendotheliosis virus. RE virus infection, however, did not affect the hepatic pyruvate carboxylase activity, indicating that inhibition of phosphoenolpyruvate carboxykinase is not due to a general inhibition of all liver enzymes. Birds given injections of UV-inactivated RE viruses or reticuloendotheliosis virus-transformed, non-virus-producing tumor cells also exhibited a reduction in phosphoenolpyruvate carboxykinase activity.
Cancer Res 1985 Oct
PMID:Inhibition of hepatic phosphoenolpyruvate carboxykinase by avian reticuloendotheliosis viruses. 299 70

Hydrazine sulfate is an anticachexia agent which interrupts host energy wasting as a result of the malignant process. An inhibitor of gluconeogenesis at the phosphoenolpyruvate carboxykinase (PEP CK) reaction, this agent has been shown in randomized, placebo-controlled, double-blind trials to improve glucose tolerance, reduce glucose turnover, increase caloric intake, and increase or stabilize weight; in single-arm controlled trials, this agent has been shown to increase appetite, improve performance status, decrease pain, diminish anorexia, normalize laboratory indices, stabilize tumor growth, induce tumor regression, and promote survival, while inducing little to no important clinical side effects. In view of its demonstrated capacity to effect anticancer response, this drug is suggested for trial as a sole agent in early drug-resistant cancer, in combination with cytotoxic and related therapies, and in conjunction with total parenteral nutrition. It is postulated that effective control of the mechanisms associated associated with cancer cachexia may contribute to control of malignant disease.
Nutr Cancer 1987
PMID:Hydrazine sulfate: a current perspective. 310 88

This study was conducted to investigate the role of tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) in inducing cancer cachexia, and the results were compared with those obtained from our previous study on Fisher 344 rats with methylcholanthrene-induced sarcoma. Three groups of male Fisher 344 rats received one of the following regimens: 4 x 10(4) IU of human recombinant TNF-alpha per rat per day subcutaneously (sc) for 5 consecutive days (n = 5), 3.5 x 10(5) U human recombinant IL-2 per rat per day sc for 14 consecutive days (n = 5), or normal saline (n = 5). The activities of both phosphoenolpyruvate carboxykinase (PEPCK) and malic enzyme (ME) were increased slightly in the IL-2 group. Furthermore, LPL activity was significantly increased in the adipose tissue of the TNF group and in the cardiac muscle of the IL-2 group, but not in that of the TNF group. These results show that there is a significant difference between the metabolic alterations seen in the tumor-bearing state and those induced by either TNF-alpha or IL-2 alone. Thus, it is unlikely that IL-2 or TNF-alpha is the sole mediator of cancer cachexia in this tumor and rat model.
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PMID:The possible role of TNF-alpha and IL-2 in inducing tumor-associated metabolic alterations. 868 Jan 18

Chronic human exposure to nonovertly toxic doses of arsenic is associated with an increased risk of cancer. Although its carcinogenic mechanism is still unknown, arsenic does not directly cause DNA damage or mutations and is therefore thought to act principally as a co-mutagen, co-carcinogen, and/or tumor promoter. Previous studies in our laboratory demonstrated that effects of low-dose arsenic (III) (arsenite) on expression of the hormone-regulated phosphoenolpyruvate carboxykinase (PEPCK) gene were strongly associated with the glucocorticoid receptor (GR)-mediated regulatory pathway. We therefore examined specifically the effects of arsenite on the biochemical function of GR in hormone-responsive H4IIE rat hepatoma cells. Completely noncytotoxic arsenite treatments (0.3-3.3 microM) significantly decreased dexamethasone-induced expression of transiently transfected luciferase constructs containing either an intact hormone-responsive promoter from the mammalian PEPCK gene or two tandem glucocorticoid response elements (GRE). Western blotting and confocal microscopy of a green fluorescent protein-tagged-GR fusion protein demonstrated that arsenite pretreatment did not block the normal dexamethasone-induced nuclear translocation of GR. These data indicate that nontoxic doses of arsenite can interact directly with GR complexes and selectively inhibit GR-mediated transcription, which is associated with altered nuclear function rather than a decrease in hormone-induced GR activation or nuclear translocation.
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PMID:Arsenic alters the function of the glucocorticoid receptor as a transcription factor. 1133 85

Our laboratory has shown previously that recombinant rainbow trout Ea4 (rtEa4)-peptide of pro-insulin-like growth factor-I (pro-IGF-I) exhibited antitumor activities against cancer cell lines derived from various human cancer tissues (Chen et al., 2002; Kuo and Chen, 2002). To confirm that rtEa4-peptide can exhibit the same spectrum of antitumor activities in fish tumor cells, we had developed permanent single-cell clones (RTH1B1A, RTH1B1D, RTH1B2A, and RTH1B2C) from a rainbow trout liver tumor induced by dibenzo[a,l]pyrene treatment. At 135 passages, the doubling time of these single-cell clones in CO2-independent medium at 20 degrees C was 3.9, 3.5, 3.0, and 4.5 d, respectively. Reverse transcription-polymerase chain reaction analysis showed that the expression of liver signature genes (e.g., aldolase B, glucose-6-phosphatase [G-6-Pase], phosphoenolpyruvate carboxykinase [PEPCK], hepatic nuclear factor-1 [HNF-I], IGF-I, IGF-II, and growth hormone [GH] receptor-2 genes) and CYP1A1 and CYP1A3 genes was detected in these four single-cell clones. Furthermore, results of in vitro colony formation assay in a soft-agar medium showed different degrees of colony formation activities among them. These results confirmed that the single-cell clones were derived from the rainbow trout liver. Treatment of RTH1B1D with recombinant trout Ea4-peptide resulted in the induction of a dose-dependent morphological change and the suppression of colony formation in a soft-agar medium. In addition, both morphological change and reduction of colony formation were also observed in permanent transfectants of RTH1B1D cells carrying a trout Ea4-peptide gene or its human counterpart, hEb-peptide gene. These results confirm our earlier observations that trout pre-IGF-I Ea4-peptide and hEb possess activities counteracting malignant properties of cancer cells in vitro.
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PMID:Development of rainbow trout hepatoma cell lines: effect of pro-IGF-I Ea4-peptide on morphological changes and anchorage-independent growth. 1531 63


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