Redox modulation of cell surface protein thiols in U937 lymphoma cells: the role of γ-glutamyl transpeptidase-dependent H2O2 production and S-thiolation

Dominici, Silvia; Valentini, Melissa; Maellaro, Emilia; Bello, Barbara Del; Paolicchi, Aldo; Lorenzini, Evelina; Tongiani, Roberto; Comporti, Mario; Pompella, Alfonso

doi:10.1016/s0891-5849(99)00111-2

Cited by 149 publications

(115 citation statements)

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“…Experimental evidence has elucidated the ability of cellular GGT to modulate crucial redox-sensitive functions, such as antioxidant/antitoxic defences and cellular proliferative/apoptotic balance, and its role in tumor progression, invasion and drug resistance has repeatedly been suggested. [20][21][22][23] GGT is constitutively expressed in several organs and is often significantly increased in malignant or premalignant lesions, where it is considered a factor conferring growth and survival advantages for the rapidly dividing neoplastic cells. 40,41 The ability of cellular GGT to affect the catabolism of extracellular GSH potentially reflects on several aspects of cell metabolism, especially through the modulation of redox status at cell surfaces and H 2 O 2 production.…”

Section: Discussionmentioning

confidence: 99%

“…Several experimental models have elucidated the ability of cellular GGT to modulate crucial redoxsensitive functions, such as antioxidant/antitoxic defences and cellular proliferative/apoptotic balance, and its role in tumor progression, invasion and drug resistance has been proposed. [20][21][22][23] In addition, a potentially interesting interpretation subsumes GGT as a biomarker of exposure to certain cancer-causing xenobiotics, including persistent organic pollutants (POPs). Based on NHANES data, Lee and colleagues 24,25 recently showed that some environmental pollutants such as lead, cadmium, dioxins or organochlorine pesticides are positively and monotonically related to serum GGT levels in the general US population.…”

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confidence: 99%

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Prospective study of the association of gamma‐glutamyltransferase with cancer incidence in women

Strasak

Pfeiffer

Klenk

et al. 2008

Intl Journal of Cancer

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Although several epidemiologic studies have shown that gammaglutamyltransferase (GGT) is associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In experimental models the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it may thus play a role in tumor progression. In the present study, we investigated the association of GGT with overall and site-specific cancer incidence in a population-based cohort of 92,843 Austrian women with 349,674 serial GGT measurements, prospectively followed-up for a median of 13.5 years. The relationship between GGT and cancer incidence was analyzed using adjusted Cox regression models with age as underlying time metric with age as underlying time metric including GGT concentrations at baseline and incorporating repeated GGT measurements as a time-dependent variable. During follow-up, 4,884 incidence cancers were observed. Compared to normal low GGT (<17.99 U/L), cancer risk was elevated for all other GGT categories (p for trend < 0.0001), with adjusted hazard ratios (95% confidence intervals) of 1.06 (0.99-1.13) for GGT levels between 18.00 and 35.99 U/L (normal high), 1.12 (1.02-1.22) for GGT levels between 36.00 and 71.99 U/L (elevated) and 1.43 (1.28-1.61) for highly elevated GGT (>72.00 U/L). Very similar results were seen when GGT was analyzed as a time-dependent variable. In cancer-site specific models, elevated GGT statistically significantly increased the risk for malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, breast and female genital organs and lymphoid and haematopoietic cancers (all, p < 0.006). Our study is the first to demonstrate in a large population-based cohort that high GGT levels significantly increased cancer risk in women.Published 2008 Wiley-Liss, Inc. This article is a US Government work, and, as such, is in the public domain in the United States of America.Key words: gamma-glutamyltransferase; cancer incidence; risk factor; epidemiology; women Gamma-glutamyltransferase (GGT), present on the external surface of most cells and in serum, is the enzyme responsible for the extracellular catabolism of glutathione (GSH), the main thiol antioxidant in mammalian cells. 1,2 In clinical practice, GGT is commonly used as a diagnostic test to assess liver dysfunction, and as a biological marker of excessive alcohol intake. 1,3,4 However, several recent epidemiologic studies have shown elevated GGT to independently influence morbidity and mortality from causes other than liver disease. Particularly, GGT was independently related to cardiovascular disease, 5-12 it correlated with most cardiovascular risk factors [13][14][15][16] and, more recently, an association with chronic kidney disease was found. 17 In addition, several large-scale studies indicate an independent role of GGT for premature death from all causes. 9,18,19 The association of GGT with cancer incidence, however, remains largely unexplored. Several ex...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Prospective study of the association of gamma‐glutamyltransferase with cancer incidence in women

Strasak

Pfeiffer

Klenk

et al. 2008

Intl Journal of Cancer

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“…Specifically, cysteinylglycine, which is one of the products of GGT action, has a strong ability to reduce Fe 3þ to Fe 2þ , which again promotes generation of free radical species. A GGT-mediated oxidative stress has been repeatedly reported, capable of inducing oxidation of lipids, [7,8] oxidation of protein thiols, [10] alterations of the normal protein phosphorylation patterns, [11] and biological effects such as the activation of transcription factors. [12,13] …”

Section: Cellular Gamma Glutamyltransferase (Ggt) and Oxidative Stresmentioning

confidence: 99%

ReviewIs Serum Gamma Glutamyltransferase a Marker of Oxidative Stress?

Lee

Blomhoff

Jacobs

2004

Free Radical Research

591

438

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The primary role of cellular gamma glutamyltransferase (GGT) is to metabolize extracellular reduced glutathione (GSH), allowing for precursor amino acids to be assimilated and reutilized for intracellular GSH synthesis. Paradoxically, recent experimental studies indicate that cellular GGT may also be involved in the generation of reactive oxygen species in the presence of iron or other transition metals. Although the relationship between cellular GGT and serum GGT is not known and serum GGT activity has been commonly used as a marker for excessive alcohol consumption or liver diseases, our series of epidemiological studies consistently suggest that serum GGT within its normal range might be an early and sensitive enzyme related to oxidative stress. For example, serum and dietary antioxidant vitamins had inverse, doseresponse relations to serum GGT level within its normal range, whereas dietary heme iron was positively related to serum GGT level. More importantly, serum GGT level within its normal range positively predicted F2-isoprostanes, an oxidative damage product of arachidonic acid, and fibrinogen and C-reactive protein, markers of inflammation, which were measured 5 or 15 years later, in dose -response manners. These findings suggest that strong associations of serum GGT with many cardiovascular risk factors and/or events might be explained by a mechanism related to oxidative stress. Even though studies on serum and/or cellular GGT is at a beginning stage, our epidemiological findings suggest that serum GGT might be useful in studying oxidative stress-related issues in both epidemiological and clinical settings.

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“…The intracellular redox environment is mainly controlled by the glutathione-redox, which is defined as the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) (1) and plays critical roles in maintaining cellular homeostasis and various physiological functions (2). The cellular glutathione-redox dynamically regulates protein functions by reversible disulfide bond formation on variety of proteins, including phosphatases, kinases, and transcription factors (3)(4)(5) and is known to protect against oxidative stress (6,7). The glutathione-redox balance in macrophages is shown to be critical for mounting innate immune responses and has also been implicated in many of the pathological conditions (2,(8)(9)(10), indicating its possible potential use as a therapeutic agent.…”

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confidence: 99%

Glutathione-Redox Balance Regulates c-rel–Driven IL-12 Production in Macrophages: Possible Implications in Antituberculosis Immunotherapy

Alam

Ghousunnissa

Nair

et al. 2010

The Journal of Immunology

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Redox modulation of cell surface protein thiols in U937 lymphoma cells: the role of γ-glutamyl transpeptidase-dependent H2O2 production and S-thiolation

Cited by 149 publications

References 49 publications

Prospective study of the association of gamma‐glutamyltransferase with cancer incidence in women

Prospective study of the association of gamma‐glutamyltransferase with cancer incidence in women

ReviewIs Serum Gamma Glutamyltransferase a Marker of Oxidative Stress?

Glutathione-Redox Balance Regulates c-rel–Driven IL-12 Production in Macrophages: Possible Implications in Antituberculosis Immunotherapy

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