Modulation of cell growth and cisplatin sensitivity by membrane gamma-glutamyltransferase in melanoma cells.
The plasma membrane enzyme gamma-glutamyltransferase (GGT) is regarded as critical for the maintenance of intracellular levels of glutathione (GSH). GGT expression has been implicated in drug resistance through elevation of intracellular GSH. The dependence of intracellular GSH on GGT expression was not conclusively ascertained. The present study was designed to investigate the role of GGT and of intracellular GSH levels in modulating proliferation and sensitivity to cisplatin of melanoma cells. GGT transfection resulted in increased growth, both in vitro and in tumour xenografts. In addition, GGT-transfected cells exhibited reduced sensitivity to cisplatin associated with lower DNA platination. A decrease in intracellular GSH levels, rather than an increase, was observed in GGT-transfected cells; moreover, in cysteine-deficient conditions, the expression of GGT did not provide transfected cells with the ability of utilising extracellular GSH. In conclusion, these results indicate that GGT activity confers a growth advantage unrelated with intracellular glutathione supply, and are consistent with the interpretation that cisplatin resistance is the consequence of modifications of cellular pharmacokinetics as a result of extracellular drug inactivation by thiol metabolites originated by GGT-mediated GSH cleavage.
Franzini
Maria
M
Dipartimento di Patologia Sperimentale BMIE, University of Pisa Medical School, Italy.
Corti
Alessandro
A
Lorenzini
Evelina
E
Paolicchi
Aldo
A
Pompella
Alfonso
A
De Cesare
Michelandrea
M
Perego
Paola
P
Gatti
Laura
L
Leone
Roberto
R
Apostoli
Pietro
P
Zunino
Franco
F
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology; D005723:gamma-Glutamyltransferase / Q000502:physiology*
D000970:Antineoplastic Agents; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D002945:Cisplatin