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)

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) isolated from Plumbago zeylanica Linn, when administered orally, at a dosage of 4 mg/kg body weight induces tumour regression in 3-methyl-4-dimethyl aminoazobenzene (3MeDAB) induced hepatoma in Wistar male rats. The purpose of this investigation was to identify the changes in the rate of glycolysis and gluconeogenesis in tumour-bearing rats and the effects of treatment with Plumbagin. The levels of certain glycolytic enzymes, namely, hexokinase; phosphoglucoisomerase; and aldolase levels increased (p < 0.001) in hepatoma bearing rats, whereas they decreased in Plumbagin administered rats to near normal levels. Certain gluconeogenic enzymes, namely, glucose-6-phosphatase and fructose-1,6-diphosphatase decreased (p < 0.001) in tumour hosts, whereas Plumbagin administration increased the gluconeogenic enzyme levels in the treated animals. These investigations indicate the molecular basis of the different biological behaviour of 3MeDAB induced hepatoma and the anticarcinogenic property of Plumbagin against hepatoma studied in rats.
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PMID:Effect of Plumbagin on some glucose metabolising enzymes studied in rats in experimental hepatoma. 826 73

We have identified cDNAs representing three hexokinase mRNAs (Hk1-sa, Hk1-sb, Hk1-sc) by screening mouse spermatogenic cell cDNA libraries with a mouse hepatoma cell line hexokinase (Hk1) cDNA [Arora KK, Fanciulli M, Pederson PL. J Biol Chem 1990; 265:6481-6488]. Although all three cDNAs show 99% identity to the somatic Hk1 cDNA sequence throughout most of their coding region, they differ from this sequence at the 5' end. They contain a common spermatogenic cell-specific sequence and a sequence unique to each cDNA immediately 5' to the common domain. However, they lack the porin-binding domain (PBD) present in this region of Hk1, used for binding to a pore-forming protein in the outer mitochondrial membrane. These observations appear to support a model proposed by others for hexokinase gene evolution in mammals. In addition, we found that Hk1-sb has an internal sequence that is not present in Hk1, Hk1-sa, or Hk1-sc. Moreover, Hk1-sa and Hk1-sb transcripts are developmentally expressed in mouse spermatogenic cells. Hk1-sa mRNA is first expressed during meiosis and continues to be present in postmeiotic germ cells, while the more abundant Hk1-sb mRNA is detected only in postmeiotic germ cells. These and other findings suggest that enzymes encoded by Hk1-sa, Hk1-sb, and Hk1-sc are present only in spermatogenic cells.
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PMID:Unique hexokinase messenger ribonucleic acids lacking the porin-binding domain are developmentally expressed in mouse spermatogenic cells. 839 93

In the mouse, a 95 kD sperm protein has been identified as a putative receptor for the zona pellucida glycoprotein ZP3. The 95 kD sperm protein is a tyrosine kinase substrate, with phosphorylation on tyrosine stimulated upon zona pellucida binding. The latter finding is observed not only in live cells but also in isolated sperm membranes and in an electroeluted 95 kD protein. Stimulation of 95 kD protein tyrosine phosphorylation by zona pellucida is completely abolished by tyrosine kinase inhibitors, which effectively inhibit the sperm acrosome reaction. Since receptor oligomerization by ZP3 is essential for acrosome reaction triggering, we hypothesized that application of an external crosslinking agent will lead to the acrosome reaction, even in the absence of natural ligand ZP3. Here, we report the generation of a mouse monoclonal antibody (mAb) raised against the 95 kD protein. This antibody, termed LL95, mimics the bioactivities of ZP3 in inhibiting sperm-zona binding and inducing the acrosome reaction. The latter depends on receptor oligomerization. Immunolocalization revealed that the LL95 antigen is restricted to the head surface in the acrosomal region of live sperm. Thus, LL95 fulfills several criteria predicted for an antibody that recognizes a sperm receptor for the zona pellucida. Recently, it was reported that the amino acid sequence of the 95 kD protein we described corresponds to a mouse hepatoma hexokinase (Kalab et al., 1994: J Biol Chem 269:3810-3817). Although both hexokinase and LL95 antigen migrate at 95 kD in nonreducing gels, we show here that LL95 does not recognize hexokinase. Identification of different proteins is clear where hexokinase is a 116 kD protein and LL95 recognizes sperm proteins of 110 and 130 kD. Moreover, mAb anti-phosphotyrosine immunoprecipitates LL95 antigen under conditions where hexokinase is absent. Use of anti-hexokinase antibodies in gamete interaction assays failed to demonstrate any effect on either sperm-zona binding or acrosome reaction triggering. Finally, antihexokinase antibodies bind to a sperm tail antigen, thus direct involvement of hexokinase in gamete interaction seems improbable.
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PMID:LL95 monoclonal antibody mimics functional effects of ZP3 on mouse sperm: evidence that the antigen recognized is not hexokinase. 857 49

The increased glucose consumption of many tumor cells depends to a large extent on the overexpression of hexokinase Type II. In a previous study we isolated and sequenced the hepatoma Type II hexokinase promoter and showed that it is activated by glucose in the highly glycolytic AS-30D hepatoma cell line under study, but not activated in control hepatocytes [Mathupala, S.P., Rempel, A. and Pedersen, P.L. (1995) J. Biol. Chem. 270, 16918-16925]. Here we report that the promoter of the hexokinase Type II gene is maximally activated by glucose at concentrations above 5 mM. Moreover, the data strongly suggest that glucose can act alone without requirement for metabolism. Also, glucose-mediated promoter activation is markedly potentiated by cAMP. This response may serve as a strategy for cancer cells to maintain the hexokinase transcription rate high to ensure an efficient glucose utilization even under conditions where carbohydrates are limiting.
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PMID:Glucose catabolism in cancer cells: regulation of the Type II hexokinase promoter by glucose and cyclic AMP. 864 58

Hexokinase type II is highly overexpressed in many cancer cells, where it plays a pivotal role in the high glycolytic phenotype. Here we demonstrate by Southern blot analysis and fluorescence in situ hybridization (FISH) that in the rapidly growing rat AS-30D hepatoma cell line, enhanced hexokinase activity is associated with at least a 5-fold amplification of the type II gene relative to normal hepatocytes. This amplification is located chromosomally, extends to the whole gene, and most likely occurs at the site of the resident gene. No rearrangement of the gene could be detected. Therefore, overexpression of hexokinase type II in AS-30D hepatoma cells may be based, at least in part, on a stable gene amplification. This is the first report describing the amplification of a hexokinase gene in a tumor cell line expressing the high glycolytic phenotype.
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PMID:Glucose catabolism in cancer cells: amplification of the gene encoding type II hexokinase. 865 77

To know the structural properties responsible for the enzymic activity of the 50-kDa C-terminal half of type II hexokinase (HKII-C) derived from rat hepatoma cell line AH130, we constructed cDNAs of HKII-C and its recombinants in which restricted regions containing highly conserved sequences, referred to as regions 2 and 3, were replaced by the corresponding regions of glucokinase. The binding domains of ATP and glucose were proposed to exist in these regions, respectively. Then, the HKII-C and chimera HKII-Cs were overexpressed in Escherichia coli BL21(DE3)pLysS. They all exhibited hexokinase activity, and their activities were inhibited by glucose-6-phosphate (Glc-6-P) competitively for ATP and uncompetitively for glucose. The replacement of region 2 of HKII-C by the corresponding region of glucokinase increased the affinity for glucose and decreased the affinity for Glc-6-P, but it did not significantly affect the affinity for ATP. In contrast, the replacement of region 3 did not cause an appreciable change in hexokinase activity. These findings suggest that region 2 is associated with the binding of ATP and Glc-6-P, and that the latter binding site is located close to the ATP binding site. In addition, region 2 was suggested to be directly related with the binding of glucose and other hexoses.
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PMID:Alteration of enzyme function of the type II hexokinase C-terminal half on replacements of restricted regions by corresponding regions of glucokinase. 866 49

We isolated highly intact and tightly coupled mitochondria from the rat ascites hepatoma cell line AH130 by disruption of the cell membrane by nitrogen cavitation. These isolated mitochondria were found to have essentially the same functional properties as rat liver mitochondria, but unlike the latter, hexokinase (HK) was bound to their membrane. Using the tumor mitochondrial preparation, we examined the source of ATP for phosphorylation of glucose by HK under conditions in which intra- and extramitochondrial ATP-generation systems operated separately or together. Results showed that the membrane-bound HK utilized ATP derived from the most efficiently operating ATP generation system, i.e., oxidative phosphorylation. However, when the rate of extramitochondrial ATP generation was much greater than that of oxidative phosphorylation, HK used ATP from the extramitochondrial ATP-generation system.
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PMID:Source of ATP for hexokinase-catalyzed glucose phosphorylation in tumor cells: dependence on the rate of oxidative phosphorylation relative to that of extramitochondrial ATP generation. 913 Oct 53

Twenty-six different hepatoma cell lines established from cancer-prone transgenic mice exhibited a close correlation between expression of the GLUT 2 glucose transporter and activation of the L-type pyruvate kinase (L-PK) gene by glucose, as judged by Northern blot analyses and transient transfection assays. The L-PK gene and a transfected L-PK construct were silent in GLUT 2(+) cells and active in GLUT 2(-) cells cultured in glucose-free medium. Transfection of GLUT 2(-) cells with a GLUT 2 expression vector restored the inducibility of the L-PK promoter by glucose, mainly by suppressing the glucose-independent activity of this promoter. Culture of GLUT 2(-) cells, in which the L-PK gene is constitutively expressed, in a culture medium using fructose as fuel selected GLUT 2(+) clones in which the L-PK gene responded to glucose. The expression of the L-PK gene in GLUT 2(-) cells cultured in the absence of glucose was correlated with a high intracellular glucose 6-phosphate (Glu-6-P) concentration while under similar culture conditions Glu-6-P concentration was very low in GLUT 2(+) cells. Consequently, a role of GLUT 2 in the glucose responsiveness of glucose-sensitive genes in cultured hepatoma cells could be to allow for Glu-6-P depletion under gluconeogenic culture conditions. In the absence of GLUT 2, glucose endogeneously produced might be unable to be exported from the cells and would be phosphorylated again to Glu-6-P by constitutively expressed hexokinase isoforms, continuously generating the glycolytic intermediates active on the L-PK gene transcription.
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PMID:Role of the GLUT 2 glucose transporter in the response of the L-type pyruvate kinase gene to glucose in liver-derived cells. 921 18

The p53 tumor suppressor is found to be mutated and abundant in a wide variety of tumors. Within tumors showing rapid growth, the Type II isoform of hexokinase is also highly expressed to facilitate high rates of glucose catabolism, which in turn promote their rapid proliferation. We previously reported isolation of the proximal promoter of the Type II hexokinase gene from the highly glycolytic hepatoma AS-30D (Mathupala, S. P., Rempel, A., and Pedersen, P. L. (1995) J. Biol. Chem. 270, 16918-16925). Here, we show that a p53 protein, exhibiting two point mutations in its cDNA, is abundantly expressed in the AS-30D hepatoma. Co-expression studies showed that p53 overexpression significantly and reproducibly activated the Type II hexokinase promoter. Two functional p53 motifs were identified within this promoter by footprint and gel retardation analyses. Presence of functional p53 response elements on the Type II hexokinase promoter and the positive regulatory effect on the promoter by the mutant p53 indicates that in rapidly growing liver tumors, and perhaps in many other tumors as well, this highly abundant p53 protein plays a role in maintaining a high glycolytic rate. This is the first report of a possible link between loss of cell cycle control in rapidly growing cancer cells and their high glycolytic phenotype.
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PMID:Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. 927 38

The herbal remedy extended by Semecarpus anacardium nut extract against Aflatoxin B1 mediated hepatocellular carcinoma was established by studies on carbohydrate metabolizing enzymes. Since some definite correlation exists between tumour progression and the activities of glycolytic and gluconeogenic enzymes, assessment of alterations in their activity can be used as successful markers of diagnosis and prognosis. The present work compares the activities of glycolytic and gluconeogenic enzymes in hepatocellular carcinoma bearing rats with drug-treated animals. An overall increase in glycolytic enzymes namely hexokinase, phosphoglucoisomerase, and aldolase with a subsequent reduction in gluconeogenic enzymes, glucose-6-phosphatase and fructose-1,6-biphosphatase was observed in plasma and liver homogenates of hepatocellular carcinoma bearing rats. The administration of Semecarpus anacardium nut extract caused a significant decrease in the activity of glycolytic enzymes and an increase in gluconeogenic enzymes' activities to near normal values in drug-treated animals.
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PMID:Modulating effect of Semecarpus anacardium Linn. nut extract on glucose metabolizing enzymes in aflatoxin B1-induced experimental hepatocellular carcinoma. 936 62


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