Glutathione influences c-Myc-induced apoptosis in M14 human melanoma cells

Annamaria Biroccio, Barbara Benassi, Giuseppe Filomeni, Sarah Amodei, Sergio Marchini, Giovanna Chiorino, Giuseppe Rotilio, Gabriella Zupi, Maria Rosa Ciriolo

Research output: Contribution to journalArticlepeer-review

Abstract

The objective of this article is to dissect the mechanisms by which the down-regulation of c-Myc induces programmed cell death in melanoma cells. In stable and doxycycline-inducible M14 melanoma cells, down-regulation of c-Myc induced apoptosis subsequent to a decrease in the intracellular reduced glutathione content and a concomitant accumulation of its oxidized form. This redox alteration was associated with a decrease of the enzyme activities of γ-glutamyl-cysteine synthetase and NADPH-dependent GSSG reductase, as well as a consequent glutathione release in the extracellular medium. Cytochrome c was released into the cytosol at very early stages of apoptosis induction, long before detectable production of reactive oxygen species and activation of caspase-9 and -3. Macroarray analysis revealed that down-regulation of c-Myc produced striking changes in gene expression in the section related to metabolism, where the expression of γ-glutamyl-cysteine synthetase and GSSG reductase was found to be significantly reduced. The addition of N-acetyl-L-cysteine or glutathione ethyl ester inhibited the apoptotic process, thus confirming the key role of glutathione in programmed cell death induced by c-Myc.

Original languageEnglish
Pages (from-to)43763-43770
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number46
DOIs
Publication statusPublished - Nov 15 2002

ASJC Scopus subject areas

  • Biochemistry

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