The development of gamma-glutamyltransferase in a pig renal-epithelial-cell line in vitro. Relationship to amino acid transport.
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ABSTRACT:
SUBMITTER: Sepulveda FV
PROVIDER: S-EPMC1153991 | biostudies-other | 1982 Nov
REPOSITORIES: biostudies-other
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Project description:Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. While the localized form of this disease can be treated surgically, advanced and metastatic stages are resistant to chemotherapies. Although more innovative treatments, such as targeted or immune-based therapies, exist, the need for new therapeutic options remains. ccRCC presents unique metabolic signatures and multiple studies have reported a significant increase in levels of reduced glutathione (GSH) and its precursors in ccRCC tumor samples compared with normal kidney tissues. These observations led us to investigate the effects of blocking the GSH pathway, particularly the gamma-glutamyltransferase 1 (GGT1) enzyme, in multiple ccRCC cell lines. In this study, we provide in vitro and in vivo evidence that GGT1/GSH pathway inhibition impacts ccRCC cell growth, through increased cell-cycle arrest. Of note, GGT1 inhibition also impairs ccRCC cell migration. Finally, pharmacologic GSH pathway inhibition decreases ccRCC cell proliferation and increases sensitivity to standard chemotherapy. Our results suggest that GGT1/GSH pathway inhibition represents a new strategy to overcome ccRCC chemoresistance. IMPLICATIONS: GGT1/GSH pathway inhibition represents a promising therapeutic strategy to overcome chemoresistance and inhibit progression of ccRCC tumors.
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Project description:Observational epidemiological evidence supports a linear and independent association between serum gamma-glutamyltransferase (GGT) concentrations and the risk of Alzheimer's disease (AD). However, the causality of this association has not been previously investigated. We sought to assess the causal nature of this association using a Mendelian randomization (MR) approach. Using inverse-variance weighted MR analysis, we assessed the association between GGT and AD using summary statistics for single nucleotide polymorphism (SNP)-AD associations obtained from the International Genomics of Alzheimer's Project of 17,008 individuals with AD and 37,154 controls. We used 26 SNPs significantly associated with GGT in a previous genome-wide association study on liver enzymes as instruments. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR. The odds ratio of AD was 1.09 (95% confidence interval, 0.98 to 1.22; p = 0.10) per one standard deviation genetically elevated GGT based on all 26 SNPs. The results were similar in both MR-Egger and weighted median MR methods. Overall, our findings cannot confirm a strong causal effect of GGT on AD risk. Further MR investigations using individual-level data are warranted to confirm or rule out causality.
| S-EPMC5915296 | biostudies-literature
Project description:alpha-(Methylamino)isobutyric acid (MeAIB) insensitive Na(+)-dependent alanine transport activity in the bovine kidney cell line NBL-1 was increased upon amino acid starvation (> or = 20% over control levels). When L-phenylalanine (3 mM) was included in the starvation medium the increase was further enhanced (> or = 85% over control levels). In cells grown in control medium the Vmax, for MeAIB-insensitive Na+/alanine co-transport was found to be 6.0 +/- 0.7 nmol/3 min per mg (Km 41 +/- 12 microM) and for L-phenylalanine-treated amino-acid-starved cells the Vmax. was 21 +/- 5 nmol/3 min per mg (Km 92 +/- 40 microM). The increase in Vmax. was prevented by cycloheximide. Substrate specificity analysis identified the L-phenylalanine-induced transport system as System B0. [35S]Methionine labelling of cells during the amino acid starvation/phenylalanine treatments resulted in the differential labelling of a protein of 78 kDa. Northern-blot analysis using a SAAT1-specific probe revealed the presence of a new transcript (3.2 kb) in RNA extracted from cells incubated in amino acid starvation medium with L-phenylalanine included. The present findings suggest a novel means of control for System B0 by the use of physiological stress. It is also proposed that SAAT1 and System-B0 transcripts have considerable sequence similarity.
| S-EPMC1137094 | biostudies-other
Project description:Active-site residues in rat kidney gamma-glutamyltransferase (EC 2.3.2.2) were investigated by means of chemical modification. 1. In the presence of maleate, the activity was inhibited by phenylmethanesulphonyl fluoride, and the inhibition was not reversed by beta-mercaptoethanol, suggesting that a serine residue is close to the active site, but is shielded except in the presence of maleate. 2. Treatment of the enzyme with N-acetylimidazole modified an amino group, exposed a previously inaccessible cysteine residue and inhibited hydrolysis of the gamma-glutamyl-enzyme intermediate, but not its formation. 3. After reaction of the enzyme successively with N-acetylimidazole and with non-radioactive iodoacetamide/serine/borate, two active-site residues reacted with iodo[(14)C]acetamide. One of these possessed a carboxy group, which formed a [(14)C]glycollamide ester, and the other was cysteine, shown by isolation of S-[(14)C]carboxymethylcysteine after acid hydrolysis. When N-acetylimidazole treatment was omitted, only the carboxy group reacted with iodo[(14)C]acetamide. 4. Isolation of the gamma-[(14)C]glutamyl-enzyme intermediate was made easier by prior treatment of the enzyme with N-acetylimidazole. The gamma-glutamyl-enzyme bond was stable to performic acid, and to hydroxylamine/urea at pH10, but was hydrolysed slowly at pH12, indicating attachment of the gamma-[(14)C]glutamyl group in amide linkage to an amino group on the enzyme. Proteolysis of the gamma-[(14)C]glutamyl-enzyme after performic acid oxidation gave rise to a small acidic radioactive peptide that was resistant to further proteolysis and was not identical with gamma-glutamyl-epsilon-lysine. 5. A scheme for the catalytic mechanism is proposed.
| S-EPMC1161375 | biostudies-other
Project description:BACKGROUND: Gamma-glutamyltransferase (GGT) regulates apoptotic balance and promotes cancer progression and invasion. Higher pretherapeutic GGT serum levels have been associated with worse outcomes in various malignancies, but there are no data for renal cell carcinoma (RCC). METHODS: Pretherapeutic GGT serum levels and clinicopathological parameters were retrospectively evaluated in 921 consecutive RCC patients treated with nephrectomy at a single institution between 1998 and 2013. Gamma-glutamyltransferase was analysed as continuous and categorical variable. Associations with RCC-specific survival were assessed with Cox proportional hazards models. Discrimination was measured with the C-index. Decision-curve analysis was used to evaluate the clinical net benefit. The median postoperative follow-up was 45 months. RESULTS: Median pretherapeutic serum GGT level was 25 U l(-1). Gamma-glutamyltransferase levels increased with advancing T (P<0.001), N (P=0.006) and M stages (P<0.001), higher grades (P<0.001), and presence of tumour necrosis (P<0.001). An increase of GGT by 10 U l(-1) was associated with an increase in the risk of death from RCC by 4% (HR 1.04, P<0.001). Based on recursive partitioning-based survival tree analysis, we defined four prognostic categories of GGT: normal low (<17.5 U l(-1)), normal high (17.5 to <34.5 U l(-1)), elevated (34.5 to <181.5 U l(-1)), and highly elevated (⩾181.5 U l(-1)). In multivariable analyses that adjusted for the effect of standard features, both continuously and categorically coded GGT were independent prognostic factors. Adding GGT to a model that included standard features increased the discrimination by 0.9% to 1.8% and improved the clinical net benefit. CONCLUSIONS: Pretherapeutic serum GGT is a novel and independent prognostic factor for patients with RCC. Stratifying patients into prognostic subgroups according to GGT may be used for patient counselling, tailoring surveillance, individualised treatment planning, and clinical trial design.
| S-EPMC4200090 | biostudies-other
Project description:gamma-Glutamyltransferase activity has been measured in yeast (Saccharomyces cerevisiae) and shown to be associated mainly with the membrane fraction. A similar level of activity is found in a wild-type strain and in gap and gpp strains, the latter mutants being defective in the general amino acid and peptide permeases respectively. The activity is inhibited in whole cells by 6-diazo-5-oxo-L-norleucine (N2O-Nle), azaserine and serine-borate complex; this inactivation seemingly acts from without, for it is similar in (i) control and dicyclohexylcarbodi-imide-treated cells and in (ii) the wild-type and a gap mutant, a treatment and a mutation that it has been shown prevents uptake of the inhibitors. Thus a major portion of the gamma-glutamyltransferase activity appears to exist in a membrane-bound form that is orientated with its gamma-glutamyl-binding site facing the outside. Yeast cells in which gamma-glutamyltransferase has been inactivated by N2O-Nle show no significant change in their rates of uptake of a variety of amino acids, dipeptides and gamma-glutamyl-amino acids. The results preclude a major, direct role for gamma-glutamyltransferase in the transport of these substrates.
| S-EPMC1153318 | biostudies-other
Project description:BackgroundGamma-glutamyltransferase (GGT) is a biomarker of liver injury. GGT has also been reported to be a marker of oxidative stress and a predictor of mortality in the general population. Hemodialysis (HD) patients suffer from oxidative stress. The aim of our study was to investigate the relationship between serum GGT levels and clinical outcomes in HD patients.MethodsA total of 1,634 HD patients were enrolled from the Clinical Research Center registry for end-stage renal disease, a prospective cohort in Korea. Patients were categorized into three groups by tertiles of serum GGT levels. The primary outcome was all-cause, cardiovascular, or infection-related mortality and hospitalization.ResultsDuring the median follow-up period of 30 months, the highest tertile of serum GGT levels had a significantly higher risk for all-cause mortality (hazard ratio (HR) 2.39, 95% confidence interval (CI), 1.55-3.69, P<0.001), cardiovascular mortality (HR 2.14, 95% CI, 1.07-4.26, P = 0.031) and infection-related mortality (HR 3.07, 95% CI, 1.30-7.25, P = 0.011) using tertile 1 as the reference group after adjusting for clinical variables including liver diseases. The highest tertile also had a significantly higher risk for first hospitalization (HR 1.22, 95% CI, 1.00-1.48, P = 0.048) and cardiovascular hospitalization (HR 1.42, 95% CI, 1.06-1.92, P = 0.028).ConclusionsOur data demonstrate that high serum GGT levels were an independent risk factor for all-cause, cardiovascular, and infection-related mortality, as well as cardiovascular hospitalization in HD patients. These findings suggest that serum GGT levels might be a useful biomarker to predict clinical outcomes in HD patients.
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Project description:Gamma-glutamyltransferase (GGT) is an established marker for proliferative/apoptotic balance and has been associated with cancer risk and prognosis. The aim of this study was to evaluate the value of pre-treatment GGT serum levels as prognostic biomarker in patients with primary uterine leiomyosarcoma (ULMS). Data of women with ULMS were extracted from a multi-center database. Pre-treatment GGT serum levels were measured and patients assigned to predefined GGT risk groups. GGT values were correlated with clinico-pathological parameters and univariate and multivariable survival analyses were performed. A total of 44 patients with ULMS were analyzed. Mean (SD) pre-therapeutic GGT serum level was 33.8 (39.8) U/L. In Figo Stage I versus II-IV mean (SD) GGT values were 28.8 (34.0) U/l and 43.5 (49.2) U/l, respectively (p?=?0.25). Five-year overall survival (OS) rates in ULMS patients with normal low versus higher GGT levels were 70% and 37%, respectively (p?=?0.043). Univariate and multivariable analyses revealed that higher GGT serum levels (p?=?0.043, p?=?0.005) and high histological grade (p?=?0.029, p?=?0.012) were independently associated with impaired OS, respectively. Higher pre-treatment GGT serum levels were independently associated with unfavorable prognosis in women with ULMS. Thus, GGT seems to be a useful novel biomarker in ULMS.
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