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The expression of gamma-glutamyltransferase in cancer cells is a factor in genomic instability, progression and drug resistance.
No full text{gamma}-Glutamyltransferase (GGT), involved in metabolism of glutathione (GSH), can promote prooxidant reactions (Dominici et al, Meth Enzymol 2005) both extra- and intracellularly, resulting e.g. in activation of NF-kB (Maellaro et al, J Cell Sci 2000). Cancer cells often overexpress GGT, along with increased resistance to cisplatin. A role of GGT in cellular supply of GSH remains questionable (Pompella et al, Biochem Pharm 2006).
We have observed that:
proliferation of GGT-transfected melanoma cells is increased, both in culture and in vivo in athymic mice,
resistance to cisplatin is also increased, but
intracellular GSH levels are decreased.
Thus, drug resistance offered by GGT is likely the result of a process of "extracellular detoxication", as previously envisaged (Paolicchi et al, Eur J Cancer 2003). On the other hand, previous studies showed that GGT can effect a redox regulation of PARP activity (Del Bello et al, FASEB J 1999), likely due to some degree of (oxidative) DNA damage. In melanoma as well as in prostatic cancer cells, we observed that:
GGT-transfected cells present with higher DNA damage levels (Comet assay),
the specific inhibition of GGT restores control levels of damage, while
DNA repair systems appear unmodified.
Expression of GGT may thus represent a critical factor in acceleration of cancer progression
Modulation of human T-lymphocyte proliferation by 4-hydroxynonenal, the bioactive product of neutrophil-dependent lipid peroxidation
No full textThe proliferative capacity of immune cells is known to be sensitive to conditions of oxidative stress and lipid peroxidation. We tested the hypothesis that activated neutrophils can induce peroxidation in extracellular lipid substrates, and evaluated the effects of 4-hydroxy-2,3-trans-nonenal (4-HNE)--the most reactive aldehydic product of lipid peroxidation--on mitogen-induced proliferation of human T lymphocytes. Neutrophils activated in the presence of extracellular lipid substrates (liposomes, cellular membranes) induced lipid peroxidation. By means of cytoimmunofluorescent labeling and confocal microscopy, the binding of 4-HNE to surface and cytoplasmic proteins of activated neutrophils was observed. Short (20 min) pre-treatment of cells with low concentrations of 4-HNE were able to dose-dependently decrease the proliferation of human peripheral blood lymphocytes challenged with PHA or anti-CD3 monoclonal antibody OKT3, as well as the proliferation of a tetanus specific human T-cell line challenged with tetanus toxoid. In these conditions, the binding of 4-HNE to surface and cytoplasmic proteins of lymphocytes was also observed. When the proliferative capacity of peripheral blood lymphocytes was monitored over several days after 4-HNE treatment and PHA challenge, a recovery and a rebound in cell proliferation was observed. Data reported indicate that the lipid peroxidation promoted by activated neutrophils can exert modulatory effects on the responsivity of human T cells, through the action of its most reactive product, 4-HNE
Cytofluorescence techniques for the visualization of distinct pools of protein thiols at the single cell level
No full text4-Hydroxynonenal (4-hydroxy-2,3-trans-nonenal; 4-HNE) is the best known and thoroughly studied aldehydic product originating in biological samples during the process of lipid peroxidation (Fig. 1) (1). The latter is an autocatalytic, self-propagating sequence of free radical reactions, ultimately resulting in the fragmentation of the carbon atom chains of unsaturated fatty acids esterified in phospholipids of cellular membranes, which can be set into motion in conditions of severe oxidative stress within the cell (2). Many of the lipid fragments thus originated are aldehydes and other carbonyl products, provided with variable reactivity towards cellular macro molecules. 4-HNE was originally identified in vitro as a specific, dialyzable, cytotoxic product of peroxidation of microsomal phospholipids (3), but subsequent studies have consistently detected it in a number of experimental conditions, in which it has been shown to exert a variety of biological actions (4), as well as in important human diseases such as atherosclerosis, neurodegeneration, and cancer (5–7) Like other α,β-unsaturated aldehydes, 4-HNE is capable of binding covalently to side chains of cysteine, histidine, lysine, and other amino acids in proteins (8), thus originating new epitopes that can be detected by suitable antibodies Fig. 2). Here a convenient procedure is described using polyclonal antibodies (PAbs) and fluorescent revelation
Protein S-cisteil-glicilazione mediata dall’attività gamma-glutamiltransferasica di membrana su proteine cellulari e dell’ambiente extracellulare
No full textProtein S-thiolating activity of plasma membrane gamma-glutamyltransferase: formation of cysteinyl-glicine mixed disulfides on cell protein and in the extracellular microenvironment
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Selective colocalization of lipid peroxidation and protein thiol loss in chemically induced hepatic preneoplastic lesions: the role of gamma-glutamyltranspeptidase activity.
No full textA number of studies indicate that cell proliferation can be modulated by changes in the redox balance of (soluble and protein) cellular thiols. Free radical processes, including lipid peroxidation (LPO), can affect such a balance, and a role for LPO in multistage carcinogenesis has been envisaged. The present study was aimed to assess the relationships between the protein thiol redox status and the LPO process in chemically induced preneoplastic tissue. The Solt-Farber's initiation-promotion model of chemical carcinogenesis in the rat liver was used. In fresh cryostat sections, preneoplastic lesions were identified by the reexpression of gamma-glutamyltranspeptidase (GGT) activity. In serial sections, different classes of protein thiols were stained; in additional sections, LPO was elicited by various prooxidant mixtures and determined thereafter by the hydroxynaphthoic hydrazide-Fast Blue B procedure. The incubation of sections in the presence of chelated iron plus substrates for GGT activity leads to the development of LPO in selected section areas closely corresponding to GGT-positive lesions, indicating the ability of GGT activity to initiate LPO. Protein-reactive thiols, as well as total protein sulfur, were decreased by 20-25% in cells belonging to GGT-positive preneoplastic nodules, suggesting the occurrence of oxidative conditions in vivo. The incubation of additional adjacent sections with the prooxidant mixture H2O2 plus iron(II), in order to induce the complete oxidation of lipid present in the section, showed a decreased basal concentration of oxidizable lipid substrate in GGT-rich areas. The decreased levels of both protein thiols and lipid-oxidizable substrate in GGT-positive nodules suggest that the observed GGT-dependent pathway of LPO initiation can be chronically operative in vivo during early stages of chemical carcinogenesis, in cells expressing GGT as part of their transformed phenotype
Enhancement of ferroptosis by boric acid and its potential use as chemosensitizer in anticancer chemotherapy
No full textFerroptosis is a form of regulated cell death (RCD) characterized by intracellular iron ion accumulation and reactive oxygen species (ROS)-induced lipid peroxidation. Ferroptosis in cancer and ferroptosis-related anticancer drugs have recently gained interest in the field of cancer treatment. Boron is an essential trace element playing an important role in several biological processes. Recent studies have described contrasting effects of boric acid (BA) in cancer cells, ranging from protective/mitogenic to damaging/antiproliferative. Interestingly, boron has been shown to interfere with critical factors involved in ferroptosis-intracellular glutathione and lipid peroxidation in the first place. Thus, the present study was aimed to verify the ability of boron to modulate the ferroptotic process in HepG2 cells, a model of hepatocellular carcinoma. Our results indicate that-when used at high, pharmacological concentrations-BA can increase intracellular ROS, glutathione, and TBARS levels, and enhance ferroptosis induced by RSL3 and erastin. Also, high BA concentrations can directly induce ferroptosis, and such BA-induced ferroptosis can add to the cytotoxic effects of anticancer drugs sorafenib, doxorubicin and cisplatin. These observations suggest that BA could be exploited as a chemo-sensitizer agent in order to overcome cancer drug resistance in selected conditions. However, the possibility of reaching suitably high concentrations of BA in the tumor microenvironment will need to be further investigated
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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