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Research Paper
Bax and Bak are Required for Cytochrome c Release During Arsenic Trioxide-Induced Apoptosis
Leta K. Nutt, Vladimir Gogvadze, Wanlaya Uthaisang, Banafsheh Mirnikjoo, David J. McConkey and Sten Orrenius
volume 4 | issue 4
April 2005Pages: 459-467
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Arsenic trioxide is a potent chemotherapeutic agent that selectively triggers apoptosis in tumor cells. Previous studies have demonstrated that arsenicals cause direct damage to mitochondria, but it is not clear that these effects initiate apoptosis. Here we used Bak-/- mouse liver mitochondria and virally immortalized Bax-/-Bak-/- mouse embryonic fibroblasts (MEFs) to investigate whether or not multidomain proapoptotic Bcl-2 family proteins were required for arsenic-induced mitochondrial damage and cell death. Near clinically achievable concentrations, arsenic stimulated cytochrome c release and apoptosis via a Bax/Bak- dependent mechanism. At higher concentrations (125 mM- 1 mM), cells died via a Bax/Bak-independent mechanism mediated by oxidative stress that resulted in necrosis. Consistent with previous reports, arsenic directly inhibited complex I of the mitochondrial electron transport chain, which resulted in mitochondrial permeability transition (MPT), the generation of reactive oxygen species (ROS), and thiol oxidation. However, these effects only occurred at concentrations of arsenic trioxide of 50 mM and higher, and the oxidative stress associated with them blocked caspase activation. Our data demonstrate for the first time that the cytochrome c release which initiates apoptosis in cells exposed to this classic mitochondrial poison occurs indirectly via the activation of Bax/Bak rather than via direct mitochondrial damage. Furthermore, the results implicate reactive oxygen species in a concentration-dependent mechanistic switch between apoptosis and necrosis.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.