Regulation of γ-glutamyltransferase in cisplatin-resistant and -sensitive colon carcinoma cells after acute cisplatin and oxidative stress exposures

Abstract

Glutathione plays an important role in drug resistance of tumor cells and in their ability to resist oxidative stress. Improved salvage of glutathione can be obtained through increased activity of γ‐glutamyltransferase (GGT), which is of importance in the maintenance of cellular glutathione homeostasis. We investigated the regulation of GGT in 2 cisplatin‐resistant and 1 cisplatin‐sensitive colon carcinoma cell lines. Enzyme activity was induced in all 3 cell lines after acute exposure to cisplatin. The elevation was significantly higher in sensitive cells (3.3‐fold) than in resistant (1.6‐ to 1.7‐fold) cells. Exposure of cells to oxidative stress generated by menadione also resulted in enzyme induction but only in cisplatin‐sensitive cells. Addition of anti‐oxidants had different effects on the 2 inductions: N‐acetylcysteine blocked the induction of both cisplatin and menadione, whereas catalase and glutathione‐ester blocked only the menadione induction. Glutathione depletion alone was not sufficient to induce GGT in these cells. The data show that GGT is regulated by multiple mechanisms during anti‐tumor drug treatment and oxidative stress and that reactive oxygen species were involved in the menadione, but not cisplatin, induction of the enzyme. Int. J. Cancer 88:464–468, 2000. © 2000 Wiley‐Liss, Inc.

Upregulation of gamma-glutamyl-transpeptidase activity and uric acid level in mixed chemical exposure: implications for mutagenic and preneoplastic events

“…The significant positive correlation (r = 0.27, p<0.05) between uric acid and GGT in the exposed group, supports earlier hypothesis that GGT may in part be a marker of oxidative stress. It has been demonstrated that primary human memory T cells expressed higher level of GGT than native T cells (Borud et al, 2000;Mikkelsen et al, 2002). This observation suggests that increased GGT expression may provide an adaptive advantage in permitting these cells to resist oxidative stress.…”

“…This appears to be in agreement with the findings of Corti et al (2010) and Singh et al (2011) that GGT provides pre-neoplastic cells with resistance to acute toxicity of carcinogens owing to its participation in phase-II detoxification of xenobiotics. Several lines of evidence indicate that the advantage may be provided by the ability of GGT to retrieve GSH constituents, which leads to increased cellular GSH or replenishment of GSH (Borud et al, 2000;Mikkelsen et al, 2002). The study of Lee et al (2004) has shown that cellular GGT catalyses the first step in degradation of extracellular glutathione.…”

Elevated serum gamma-glutamyltransferase is associated with an increased risk of oesophageal carcinoma in a cohort of 8,388,256 Korean subjects

“…GGT plays a pivotal role in the extracellular catabolism of glutathione, a powerful antioxidant, and is upregulated in response to oxidative stress in epithelial and cancer cells. Accordingly, the transcription of GGT is increased after exposure to oxidants [23,24]. It has been suggested that elevation of GGT is an adaptive response of cancer cells for protection against oxidative stress [25].…”

Glutathione S-conjugates as prodrugs to target drug-resistant tumors

“…Oxidative stress has been shown to induce γGT expression (Kugelman et al, 1994; Knickelbein et al, 1996; Liu et al, 1998; Borud et al, 2000; Roomi et al, 2006). High γGT expression protects melanoma cells from hydrogen peroxide or ascorbic acid induced oxidative stress (Giommarelli et al, 2008).…”