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

Annamaria Biroccio1, Barbara Benassi, Giuseppe Filomeni

  • 1Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro, 00158 Rome, Italy. biroccio@ifo.it

The Journal of Biological Chemistry
|September 13, 2002
PubMed

Insights

Down-regulating c-Myc in melanoma cells triggers apoptosis by altering glutathione redox balance. This involves reduced glutathione levels and impaired enzyme activity, highlighting glutathione

Area of Science:

  • Molecular Biology
  • Cell Death Research
  • Cancer Cell Metabolism

Background:

  • The c-Myc oncogene plays a critical role in cell proliferation and survival.
  • Understanding c-Myc's role in melanoma cell death is crucial for targeted therapies.
  • Melanoma cells exhibit unique metabolic vulnerabilities that can be exploited.

Purpose of the Study:

  • To elucidate the mechanisms by which c-Myc down-regulation induces programmed cell death (apoptosis) in melanoma.
  • To investigate the role of cellular redox balance and glutathione metabolism in c-Myc-mediated apoptosis.
  • To identify key metabolic pathways affected by c-Myc down-regulation in melanoma.

Main Methods:

  • Utilized stable, doxycycline-inducible M14 melanoma cells for c-Myc down-regulation studies.
  • Assessed intracellular reduced and oxidized glutathione levels and extracellular glutathione.
  • Measured gamma-glutamyl-cysteine synthetase and GSSG reductase enzyme activities.
  • Performed macroarray analysis to examine gene expression changes.
  • Investigated the effect of N-acetyl-l-cysteine and glutathione ethyl ester on apoptosis.

Main Results:

  • c-Myc down-regulation induced apoptosis, preceded by decreased intracellular reduced glutathione and increased oxidized glutathione.
  • Enzyme activities of gamma-glutamyl-cysteine synthetase and NADPH-dependent GSSG reductase were reduced, leading to glutathione release.
  • Cytochrome c was released early in apoptosis, independent of reactive oxygen species or caspase activation.
  • Gene expression analysis revealed significant down-regulation of gamma-glutamyl-cysteine synthetase and GSSG reductase.
  • Supplementation with N-acetyl-l-cysteine or glutathione ethyl ester inhibited c-Myc-induced apoptosis.

Conclusions:

  • Glutathione depletion and redox alteration are key mediators of c-Myc-induced apoptosis in melanoma cells.
  • c-Myc regulates genes involved in glutathione metabolism, impacting cellular redox homeostasis.
  • Targeting glutathione metabolism represents a potential therapeutic strategy for melanoma treatment.

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