Cellular response to oxidative stress and ascorbic acid in melanoma cells overexpressing gamma-glutamyltransferase.
The extracellular gamma-glutamyltransferase-mediated metabolism of glutathione has been implicated in prooxidant events which may have impact on cellular functions including drug resistance. This study was performed in two GGT-transfected melanoma clones to explore the hypothesis that GGT expression in tumour cells is implicated in modulation of cell behaviour under stress conditions. Our results show that GGT-overexpression in melanoma cells was associated with resistance to oxidative stress produced by prooxidant agents such as hydrogen peroxide and ascorbic acid. In GGT-overexpressing cells, ability to tolerate oxidative stress was evidenced by the presence of a moderate level of ROS and lack of DNA damage response following treatment with H(2)O(2). Cellular response to oxidative stress induced by ascorbic acid was detectable only in the clone with low GGT activity which also exhibited an increased susceptibility to apoptosis. The increased resistance of the GGT-overexpressing clone was not related to intracellular GSH content but rather to the increased expression of catalase and to a reduced efficiency of iron-mediated formation of toxic free radicals. Taken together, these findings are consistent with a contribution of GGT in the mechanisms of drug resistance, because induction of oxidative stress is a relevant event in the apoptotic response to cytotoxic agents.
Giommarelli
Chiara
C
Preclinical Chemotherapy and Pharmacology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, Milan, Italy.
Corti
Alessandro
A
Supino
Rosanna
R
Favini
Enrica
E
Paolicchi
Aldo
A
Pompella
Alfonso
A
Zunino
Franco
F
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D001205:Ascorbic Acid / Q000494:pharmacology*; D015153:Blotting, Western; D002374:Catalase / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology*; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
D000975:Antioxidants; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D002374:Catalase; D005723:gamma-Glutamyltransferase; D001205:Ascorbic Acid