Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-two plasma free amino acid contents from 22 primary liver cancer (PLC) patients were assayed by means of HPLC and compared with those from 16 normal subjects. The results showed that in PLC patients, plasma total amino acid (TAA), branched chain amino acid (BCAA), glycogenic amino acid, glutamine, histidine and arginine were lowered, while plasma aromatic amino acid (AAA) and methionine did not decrease significantly resulting in the BCAA/AAA ratio decline. Comparing 8/22 subclinical and 14/22 clinical liver cancers with healthy controls respectively, it was found that there was a decrease of plasma TAA, glutamine, arginine, histidine, BCAA and BCAA/AAA ratio, and an increase of tyrosine, in subclinical stage of PLC. It suggests that alteration of most amino acids occur in the early stage of PLC and become more obvious in the moderate and late stages. The changes of plasma amino acid contents in PLC were different from those in chronic liver diseases. The alteration of plasma amino acid contents in subclinical stage of PLC suggests that the disturbance of amino acid metabolism be resulted from malignancy. Correction of the amino acid metabolic disturbance in PLC patients may enhance the inhibition of tumor growth and improve the host metabolism and anti-cancer effect.
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PMID:[Alteration of plasma amino acid content in primary liver cancer patients]. 283 57

Sequence-specific resonance assignments provide the basis for interpreting multidimensional NMR spectra and for determining 3D structures of proteins from these data. We have developed an improved strategy for determining these sequence-specific NMR assignments in small proteins and applied this method in determining proton and nitrogen resonance assignments for an 8.2-kDa engineered domain (the Z-domain) of the cell wall protein A of Staphylococcus aureus. First, HCCNH-TOCSY [Lyons, B. A. & Montelione, G.T. (1993) J. Magn. Reson. 101B, 206] data were used together with 2D 2QF-COSY, TOCSY, and 15N-HSQC data to identify amino acid spin systems. Most asparagine and glutamine spin systems were also identified uniquely from these triple-resonance data. Next, complementary HCC(CO)-NH-TOCSY [Montelione, G. T., et al. (1992) J. Am. Chem. Soc. 114, 10975] data were used to identify sequential connections from the aliphatic H alpha, H beta, H gamma, H delta, and H epsilon resonances of residue i to the amide and nitrogen resonances of residue i + 1. By combined analysis of HCCNH-TOCSY and HCC(CO)NH-TOCSY spectra we have determined most of the proton and nitrogen resonance assignments for the Z-domain. This represents the first example of the use of this triple-resonance technique to determine extensive resonance assignments in a small protein.
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PMID:An improved strategy for determining resonance assignments for isotopically enriched proteins and its application to an engineered domain of staphylococcal protein A. 839 17

The effect of glucocorticoid receptor on glutaminase gene expression and related glutamine metabolism was studied in proximal tubule-like LCC-PK1-F+ cells. These cells express functional glucocorticoid receptors as demonstrated by immunoreactivity with antiglucocorticoid receptor antibody, specific ligand binding, and a 14-fold increase in chloramphenicol acetyltransferase (CAT) reporter gene activity after exposure to dexamethasone (10(-6)M). Dexamethasone exposure for 18 h increased glutaminase mRNA and activity by 32 and 42%, respectively (both P< 0.05, paired t-test), associated with a small (9%) but significant increase in glutamine utilization (P<0.05). In an effort to elicit a greater response, endogenous glucocorticoid receptors were supplemented by transfecting cells with a plasmid, pMAMGR, expressing the rat glucocorticoid receptor gene. Transfected cells expressed a 39-fold increase in CAT activity with dexamethasone treatment, confirming a higher level of functional receptors, but glutaminase mRNA and activity were now decreased by 34 and 32%, respectively, associated with a 15% fall in glutamine utilization after 18-h exposure to dexamethasone. This biphasic response in glutaminase gene expression was mirrored by glucocorticoid receptor mRNA that increased 41% after dexamethasone in LLC-PK(1)-F+ cells, but decreased 63% after transfection (both P<0.05). These findings are consonant with glucocorticoid receptor gene modulation of glutaminase gene expression and glutamine utilization.
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PMID:Coordinate modulation of glucocorticoid receptor and glutaminase gene expression in LLC-PK1-F+ cells. 863 63

Amino acid transporter B(0)/ASC transporter 2 (ATB(0)/ASCT2) is responsible for most glutamine uptake in human hepatoma cells. Because this transporter is not expressed in normal hepatocytes, we hypothesized that its expression is necessary for growth of human liver cancer cells. To test this hypothesis, Sloan Kettering hepatoma (SK-Hep) cells were stably transfected with an inducible 1.3-kb ATB(0)/ASCT2 antisense RNA expression plasmid under the transcriptional control of mifepristone, a synthetic steroid. Induced antisense RNA expression in monolayer cultures decreased ATB(0)/ASCT2 mRNA levels by 73% and glutamine transport rates by 65% compared with controls after 24 h, leading to a 98% decrease in cell number after 48 h. Cellular death was attributable to apoptosis based on cellular blebbing, caspase-3 activation, vital dye and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and poly-(ADP-ribose) polymerase (PARP) cleavage. Transporter knockdown also markedly increased activities of caspases-2 and -9, marginally enhanced caspase-8 activity, and dramatically increased ASCT1 mRNA levels, presumably as a futile compensatory response. Apoptosis elicited via transporter silencing was not attributable to the double-stranded RNA-dependent protein kinase R (PKR) pathway. For comparison, glutamine deprivation also caused apoptotic cell death but with slower temporal kinetics, stimulated caspases-2 and -3 but not caspases-8 or -9 activities, and led to considerable PARP cleavage. Thus ASCT2 suppression exerts proapoptotic effects transcending those of glutamine starvation alone. We conclude that ATB(0)/ASCT2 expression is necessary for SK-Hep cell growth and viability and suggest that it be further explored as a selective target for human hepatocellular carcinoma.
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PMID:Inducible antisense RNA targeting amino acid transporter ATB0/ASCT2 elicits apoptosis in human hepatoma cells. 1456 74

Previous studies identified amino acid (aa) substitutions of the hepatitis C virus core region of genotype 1b (HCV-1b core region) and elevated serum alpha-fetoprotein (AFP) levels as predictors of poor virologic response to pegylated interferon (PEG-IFN) plus ribavirin (RBV), and also as risk factors for hepatocarcinogenesis. The present study evaluated the impact of aa substitutions of HCV-1b core region on AFP, as a surrogate marker of hepatocarcinogenesis, on AFP levels in 569 Japanese patients with HCV-1b but without HCC, and investigated the predictive factors of elevated AFP (> or =11 microg/L). High AFP levels were detected in 27.4% of the patients. The rate of hepatocarcinogenesis in a group of 109 patients who received IFN monotherapy and followed-up for 15 years, was significantly higher in patients with abnormal than normal AFP. Multivariate analysis of 569 patients identified fibrosis stage (F3,4), aspartate aminotransferase (> or =76 IU/L), substitution of aa 70 (glutamine or histidine), and platelet count (<15.0 x 10(4)/microl) as significant determinants of elevated AFP. In 49 patients with abnormal AFP levels and substitutions at aa 70 who were treated with PEG-IFN + RBV, the rate of normalization of AFP was significantly lower in non-virological responders (28.6%) than in transient (71.4%) and sustained (100%) virological responders. The results indicated that substitution of aa 70 of HCV-1b core region is an important predictor of elevated AFP in non-HCC patients, and that eradication of the mutant virus normalizes AFP. The results highlight the importance of eradication of mutant type virus of aa 70 for reducing the risk of hepatocarcinogenesis.
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PMID:Substitution of amino acid 70 in the hepatitis C virus core region of genotype 1b is an important predictor of elevated alpha-fetoprotein in patients without hepatocellular carcinoma. 1855 9

The substitution of amino acid (aa) 70 of arginine for glutamine and/or that of aa91 of leucine for methionine in the core protein in patients infected with hepatitis C virus (HCV) genotype 1b is associated with a poor response to pegylated interferon and ribavirin. Factors influencing these substitutions were sought in 1,097 patients infected with HCV-1b who had not received antiviral treatment. HCV variants with Arg70 and Leu91 (wild-type) decreased, while those with Gln70 and/or Met91 (mutant types) increased with age (P < 0.001). Of the 1,097 patients, 464 (42.3%) were infected with the Gln70 variant and the remaining 633 patients with the Arg70 variant. The proportion of patients with the Gln70 variant increased with the severity of liver disease (P < 0.001), elevated gamma-glutamyl transpeptidase (gamma-GTP) levels (P < 0.001) and a decrease in platelet count (P = 0.008). In univariate analysis patients with hepatocellular carcinoma, elevated aspartate aminotransferase (AST > or = 58 IU/L) and gamma-GTP (> or =61 IU/L), and decreased albumin levels (<3.9 g/dl) were more frequent in the patients with the Gln70 variant than the Arg70 variant (P = 0.003, 0.005, <0.001, and 0.031, respectively). In multivariate analysis HCC (odds ratio 1.829 [95% confidence interval 1.147-2.917]) and gamma-GTP > or =61 IU/L (1.647 [1.268-2.139]) increased the risk for the Gln70 variant. In conclusion, the substitution of amino aa70 of Arg for Gln in patients infected with HCV-1b increases with age, and it is associated with severe liver disease accompanied by elevated AST and gamma-GTP levels, as well as the development of hepatocellular carcinoma.
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PMID:Influence of amino-acid polymorphism in the core protein on progression of liver disease in patients infected with hepatitis C virus genotype 1b. 1995 Feb 30

Primary liver sarcomatous carcinomas (PLSCs) are very aggressive tumors. They are characterized by a fast clinical course, and therefore need a prompt histological diagnosis. Here, we report two cases of PLSC. One arises in a non-cirrhotic liver and the other in cirrhosis, with differences in onset and histological features. Special emphasis is put on the expression of albumin and HCC markers, and their possible usefulness in the diagnosis. The English literature of the last 20 years was revised (92 cases). Immunohistochemistry was performed manually or automatically; in situ hybridization (ISH) technique for albumin mRNA detection was carried out. The sarcomatoid components in both cases were immunoreactive for K8/18, Glutamine Synthetase and EZH2, and negative for Glypican 3, SMA, caldesmon, desmin, DOG-1, CD34, CD31, CD117, CD56, and alpha-fetoprotein. The detection of albumin mRNA by ISH was negative in the sarcomatoid component in both cases. PLSC represents a diagnostic challenge for pathologists, especially in its "pure" form: neither albumin mRNA detection nor HCC markers are useful for the diagnosis: positivity for K8/18 and the negativity for the mesenchymal markers seem to represent the main tools for the histological diagnosis.
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PMID:Primary liver sarcomatous carcinoma: report of two cases and review of the literature. 2348 78

Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor-positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2(+) cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors.
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PMID:Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. 2452 1

Glutamine is an essential amino acid for malignant tumor cells. Glutaminase that metabolizes glutamine reaches a maximum expression in tumors immediately before the maximum proliferation rate. Tumor cells grow at different rates during the day. We postulated that the activity of glutaminase in tumor cells is subject to the regulation of circadian clock gene. We measured glutaminase by western blot analysis and circadian clock gene expression by real-time polymerase chain reaction in the liver and tumor cells at six equispaced time points of the day in individual mice of a 12/12 h light/dark schedule. The results showed that the tumor-bearing mice, under normal diurnal conditions, are circadianly entrained, as reflected by the normal host locomotor activity rhythms and rhythmic liver clock gene expression. The tumors within these mice are also circadianly organized, as reflected by circadian clock gene (Bmal1) expression. What is most remarkable is that kidney-type glutaminase also showed circadian rhythms in the same pattern with tumor circadian clock gene expression in liver cancer xenograft model, indicating that conditionally inhibiting glutaminase activity may provide a new target for cancer therapy.
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PMID:Circadian clock gene expression regulates cancer cell growth through glutaminase. 2468 85

Hyperammonemia and severe amino acid imbalances play central role in hepatic encephalopathy (HE). In the article is demonstrated that the main source of ammonia in cirrhotic subjects is activated breakdown of glutamine (GLN) in enterocytes and the kidneys and the main source of GLN is ammonia detoxification to GLN in the brain and skeletal muscle. Branched-chain amino acids (BCAA; valine, leucine, and isoleucine) decrease due to activated GLN synthesis in muscle. Aromatic amino acids (AAA; phenylalanine, tyrosine, and tryptophan) and methionine increase due to portosystemic shunts and reduced ability of diseased liver. The effects on aminoacidemia of the following variables that may affect the course of liver disease are discussed: nutritional status, starvation, protein intake, inflammation, acute hepatocellular damage, bleeding from varices, portosystemic shunts, hepatic cancer, and renal failure. It is concluded that (1) neither ammonia nor amino acid concentrations correlate closely with the severity of liver disease; (2) BCAA/AAA ratio could be used as a good index of liver impairment and for early detection of derangements in amino acid metabolism; (3) variables potentially leading to overt encephalopathy exert substantial but uneven effects; and (4) careful monitoring of ammonia and aminoacidemia may discover important break points in the course of liver disease and indicate appropriate therapeutic approach. Of special importance might be isoleucine deficiency in bleeding from varices, arginine deficiency in sepsis, and a marked rise of GLN and ammonia levels that may appear in all events leading to HE.
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PMID:Ammonia and amino acid profiles in liver cirrhosis: effects of variables leading to hepatic encephalopathy. 2522 Aug 75


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