Modulation of cell growth and cisplatin sensitivity by membrane γ-glutamyltransferase in melanoma cells

Maria Franzini, Alessandro Corti, Evelina Lorenzini, Aldo Paolicchi, Alfonso Pompella, Michelandrea De Cesare, Paola Perego, Laura Gatti, Roberto Leone, Pietro Apostoli, Franco Zunino

Research output: Contribution to journalArticle

Abstract

The plasma membrane enzyme γ-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.

Original languageEnglish
Pages (from-to)2623-2630
Number of pages8
JournalEuropean Journal of Cancer
Volume42
Issue number15
DOIs
Publication statusPublished - Oct 2006

Keywords

  • γ-Glutamyltransferase
  • Cisplatin
  • Cysteine
  • Drug resistance
  • Glutathione
  • Melanoma

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

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  • Cite this

    Franzini, M., Corti, A., Lorenzini, E., Paolicchi, A., Pompella, A., De Cesare, M., Perego, P., Gatti, L., Leone, R., Apostoli, P., & Zunino, F. (2006). Modulation of cell growth and cisplatin sensitivity by membrane γ-glutamyltransferase in melanoma cells. European Journal of Cancer, 42(15), 2623-2630. https://doi.org/10.1016/j.ejca.2006.04.016