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

  • We have investigated the role of reactive oxygen species and thiol-oxidizing agents in the induction of cell death and have shown that adenocarcinoma gastric (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. We show that p53 is activated in response to diamide treatment by the oxidative induction of the Trx1/p38(MAPK) 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 in tumor histotypes resistant to ROS-producing chemotherapeutics.

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Metadaten
Author:Sara Piccirillo, Giuseppe FilomeniORCiD, Bernhard BrüneORCiD, Giuseppe Rotilio, Maria R. CirioloORCiD
URN:urn:nbn:de:hebis:30:3-764851
DOI:https://doi.org/https://doi.org/10.1074/jbc.M109.014837
ISSN:0021-9258
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/19643729
Parent Title (English):Journal of biological chemistry
Publisher:American Society for Biochemistry and Molecular Biology Publications
Place of publication:Bethesda, Md
Document Type:Article
Language:English
Date of Publication (online):2021/01/04
Year of first Publication:2009
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/02/29
Volume:284.2009
Issue:40
Page Number:13
First Page:27721
Last Page:27733
Institutes:Medizin
Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Fachübergreifende Einrichtungen / Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International