Redox mechanisms involved in the selective activation of Nrf2-mediated resistance versus p53-dependent apoptosis in adenocarcinoma cells

Sara Piccirillo, Giuseppe Filomeni, Bernhard Brüne, Gluseppe Rotilio, Maria R. Ciriolo

Research output: Contribution to journalArticle

Abstract

We have investigated the role of reactive oxygen species and thiol-oxidizing agents in the induction of cell death and have shownthatadenocarcinomagastric(AGS)cells respond differently to the oxidative challenge according to the signaling pathways activated. In particular, apoptosis in AGS cells is induced via the mitochondrial pathway upon treatment with thiol-oxidizing agents, such as diamide. Apoptosis is associated with persistent oxidative damage, as evidenced by the increase in carbonylated proteins and the expression/activation of DNA damage-sensitive proteins histone H2A.X and DNA-dependent protein kinase. Resistance to hydrogen peroxide is instead associated with Keap1 oxidation and rapid translocation of Nrf2 into the nucleus. Sensitivity to diamide and resistance to hydrogen peroxide are correlated with GSH redox changes, with diamide severely increasing GSSG, and hydrogen peroxide transiently inducing protein-GSH mixed disulfides. Weshow that p53 is activated in response to diamide treatment by the oxidative induction of the Trx1/p38MAPK signaling pathway. Similar results were obtained with another carcinoma cell line, CaCo2, indicating that these findings are not limited to AGS cells. Our data suggest that thiol-oxidizing agents could be exploited as inducers of apoptosis intumorhistotypes resistant toROS-producing chemotherapeutics.

Original languageEnglish
Pages (from-to)27721-27733
Number of pages13
JournalJournal of Biological Chemistry
Volume284
Issue number40
DOIs
Publication statusPublished - Oct 2 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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