Dominici S, Valentini M, Maellaro E, Del Bello B, Paolicchi A, Lorenzini E, Tongiani R, Comporti M, Pompella ARedox modulation of cell surface protein thiols in U937 lymphoma cells: the role of gamma-glutamyl transpeptidase-dependent H2O2 production and S-thiolation. Free Radic Biol Med 27: 623-635

Institute of General Pathology, University of Siena, Italy.
Free Radical Biology and Medicine (Impact Factor: 5.74). 10/1999; 27(5-6):623-35. DOI: 10.1016/S0891-5849(99)00111-2
Source: PubMed


The expression of gamma-glutamyl transpeptidase (GGT), a plasma membrane ectoenzyme involved in the metabolism of extracellular reduced glutathione (GSH), is a marker of neoplastic progression in several experimental models, and occurs in a number of human malignant neoplasms and their metastases. Because it favors the supply of precursors for the synthesis of GSH, GGT expression has been interpreted as a member in cellular antioxidant defense systems. However, thiol metabolites generated at the cell surface during GGT activity can induce prooxidant reactions, leading to production of free radical oxidant species. The present study was designed to characterize the prooxidant reactions occurring during GGT ectoactivity, and their possible effects on the thiol redox status of proteins of the cell surface. Results indicate that: (i) in U937 cells, expressing significant amounts of membrane-bound GGT, GGT-mediated metabolism of GSH is coupled with the extracellular production of hydrogen peroxide; (ii) GGT activity also results in decreased levels of protein thiols at the cell surface; (iii) GGT-dependent decrease in protein thiols is due to sulfhydryl oxidation and protein S-thiolation reactions; and (iv) GGT irreversible inhibition by acivicin is sufficient to produce an increase of protein thiols at the cell surface. Membrane receptors and transcription factors have been shown to possess critical thiols involved in the transduction of proliferative signals. Furthermore, it was suggested that S-thiolation of cellular proteins may represent a mechanism for protection of vulnerable thiols against irreversible damage by prooxidant agents. Thus, the findings reported here provide additional explanations for the envisaged role played by membrane-bound GGT activity in the proliferative attitude of malignant cells and their resistance to prooxidant drugs and radiation therapy.

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Available from: Alfonso Pompella, Nov 14, 2014
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    • "Pro-oxidant reactions produced by GGT may contribute to the 'persistent oxidative stress' described as a factor in genomic instability and carcinogenesis (Stark et al, 1988, 1994; Corti et al, 2010). Next to the promotion of carcinogenesis, GGT seems to induce mutagenesis , modulate cellular proliferation and apoptotic balance by its redox-sensitive function (Dominici et al, 1999; Pompella et al, 2007; Corti et al, 2009). Therefore, it can be reasonably speculated that tissue expression of GGT in EOC might have a direct effect on tumour progression and aggressive tumour behaviour. "
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    ABSTRACT: Background: Gamma-glutamyltransferase (GGT) – a membrane-bound enzyme crucially involved in the cell's detoxification pathway and apoptotic balance – is involved in tumour development, progression and chemotherapy resistance. Elevated GGT serum levels are associated with increased cancer risk in women and worse prognosis in gynaecologic cancers. The present study investigated the prognostic role of GGT in ovarian cancer patients. Methods: In this multicenter study, pre-therapeutic GGT levels were ascertained in 634 consecutive patients with epithelial ovarian cancer (EOC, n=567) and borderline tumour of the ovary (BTO, n=67). Gamma-glutamyltransferase serum levels were associated with clinicopathological parameters and uni- and multivariate survival analyses were performed. Immunohistochemistry of GGT was performed in ovarian cancer tissue and correlated with GGT serum levels. Results: Pre-therapeutic GGT serum levels were higher in patients with EOC (28.56 (38.24) U l−1) than in patients with BTO (20.01 (12.78) U l−1, P=0.01). High GGT serum levels were associated with advanced FIGO stage (P<0.001) and with worse overall survival in univariate (P<0.001) and multivariable analysis (P=0.02, HR 1.2 (1.1–1.5)). We further investigated the association between systemic GGT serum levels and local GGT expression in EOC tumour tissue and observed an association between these two parameters (P=0.03). Conclusion: High pre-therapeutic GGT serum levels are associated with advanced tumour stage and serve as an independent prognostic marker for worse overall survival in patients with EOC. Gamma-glutamyltransferase expression in ovarian cancer tissue is reflected in GGT serum levels.
    Full-text · Article · Aug 2013 · British Journal of Cancer
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    • "GSH was shown to have antioxidant properties, associated with its extracellular hydrolysis to an exceptionally active thiol, cysteinylglycine (Cys-Gly) (Scheme 1). This thiol dipeptide is characterized by lower pK a of –SH group than GSH, what facilitates reactive oxygen species generation during reduction of metal cations (Fe 3+ ) [5] (Scheme 2). Since γ-glutamyl transpeptidase is indispensable for GSH resynthesis in the cell, it "
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    ABSTRACT: Toxicity of drugs and radiation in the cells is largely dependent on the level of thiols. In the present studies, an attempt has been made to inhibit γ-glutamyl transpeptidase (γGT) activity in EAT-bearing animals tissue. We have expected that administration of γGT inhibitors: acivicin and 1,2,3,4-tetrahydroisoquinoline (TIQ) may influence GSH/γ-glutamyl transpeptidase (γGT) system in the regulation of cysteine concentration and anaerobic cysteine metabolism in normal and cancer cells. Development of Ehrlich ascites tumor in mice enhances peroxidative processes, diminishes levels of nonprotein thiols (NPSH) and sulfane sulfur, and lowers activities of enzymes involved in its formation and transfer in the liver and kidney. Although γGT inhibitors further decrease NPSH level, they increase cysteine and sulfane sulfur levels. This means that upon γGT inhibition, cysteine can be efficiently acquired by normal liver and kidney cells via another pathway, that is so productive that sulfane sulfur level and intensity of anaerobic cysteine metabolism even rise.
    Full-text · Article · Apr 2012 · The Scientific World Journal
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    • "The enzyme plays a role both in detoxification of poisonous compounds (Ishikawa et al., 1967; Meister, 1988) and the normal metabolism of biologically active compounds such as leukotrienes and prostaglandins (Cagen et al., 1976; Anderson et al., 1982; Meister, 1988; Ishikawa, 1992; Carter et al., 1997). ␥-GT is also an important enzyme that modulates the redox status of thiols in the plasma membrane proteins (Del Bello et al., 1999; Dominici et al., 1999) because one of the products of the ␥-GT reaction, Cys-Gly, contains a highly reactive thiol capable of producing active oxygen species by participating in the Fenton reaction with iron ions (Halliwell and Gutteridge, 1989). "
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    ABSTRACT: Croton membranaceus root and leaf extracts are used in the Bahamas to aromatize tobacco, in Nigeria to improve digestion, and in Ghana, for benign prostate hyperplasia. Despite claims of success there is paucity of information on its toxicity. The aim of this study was to determine if Croton membranaceus has acute toxicity properties. Roots were air-dried in a solar dryer for one week before milling. The powder was extracted with 96% ethanol, freeze-dried and re-extracted with distilled water and freeze-dried. 15 male Sprague-Dawley rats (180-200 g) were divided equally into 2 treatment groups [low dose (LD) and high dose (HD)], plus a control group (C). LD and HD received 1500 and 3000 mg/kg b.wt. Croton membranaceus aqueous extract, respectively, one time and observed for 14 days. Haematological [Full Blood Count and haemoglobin (Hb)], biochemical [bilirubin, alanine aminotransferase (ALA), aspartate aminotransferase (AST), total protein, albumin, globulin, alkaline phosphatise (ALP), γ-glutamyltranspetidase (GGT), urea, creatinine, creatinine kinase - Muscle and Brain (CK-MB), creatinine kinase - Total (CK-R)] examinations were performed. Control group's CK-MB (5444±534 U/L) and LD group CK-MB (4014±1016 U/L) were significantly different (p<0.05). Control and the HD group CK-MB (3955±1135 U/L) were significantly different (p<0.05). Both LD and HD CK-R levels (697±197U/L and 732±203 U/L, respectively), were lower than the control (1139±220 U/L) at 48 h and 14 days (p<0.05, p<0.05, respectively). γ-GT levels of the HD group was 4.8±0.4 U/L compared to the Control group value of 0.9±0.2 U/L (p<0.05). Taking all factors into consideration, Croton membranaceus ingestion does not produce general acute toxicity. However, its creatinine kinase lowering ability could be explored.
    Full-text · Article · Feb 2011 · Journal of ethnopharmacology
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