α-Tocopheryl succinate causes mitochondrial permeabilization by preferential formation of Bak channels

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Title α-Tocopheryl succinate causes mitochondrial permeabilization by preferential formation of Bak channels
Author Prochazka, Lubomir; Dong, Lan-feng; Valis, Karel; Freeman, Ruth; Ralph, Stephen John; Turanek, Jaroslav; Neuzil, Jiri
Journal Name Apoptosis
Editor Mels Sluyser
Year Published 2010
Place of publication United States
Publisher Springer
Abstract Mitocans are drugs selectively killing cancer cells by destabilizing mitochondria and many induce apoptosis via generation of reactive oxygen species (ROS). However, the molecular events by which ROS production leads to apoptosis has not been clearly defined. In this study with the mitocan α-tocopheryl succinate (α-TOS) the role of the Bcl-2 family proteins in the mechanism of malignant cell apoptosis has been determined. Exposure of several different cancer cell lines to α-TOS increased expression of the Noxa protein, but none of the other proteins of the Bcl-2 family, an event that was independent of the cellular p53 status. α-TOS caused a profound conformational change in the pro-apoptotic protein, Bak, involving oligomerization in all cell types, and this also applied to the Bax protein, but only in non-small cell lung cancer cells. Immunoprecipitation studies indicated that α-TOS activates the two BH1-3 proteins, Bak or Bax, to form high molecular weight complexes in the mitochondria. RNAi knockdown revealed that Noxa and Bak are required for α-TOS-induced apoptosis, and the role of Bak was confirmed using Bak- and/or Bax-deficient cells. We conclude that the major events induced by α-TOS in cancer cells downstream of ROS production leading to mitochondrial apoptosis involve the Noxa-Bak axis. It is proposed that this represents a common mechanism for mitochondrial destabilization activated by a variety of mitocans that induce accumulation of ROS in the early phases of apoptosis.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1007/s10495-010-0482-z
Copyright Statement Copyright 2010 Springer Netherlands. This is an electronic version of an article published in Apoptosis Volume 15, Issue 7, 782-794, 2010 Apoptosis is available online at: http://www.informaworld.com/smpp/ with the open URL of your article
Volume 15
Issue Number 7
Page from 782
Page to 794
ISSN 1360-8185
Date Accessioned 2010-08-09
Date Available 2011-03-08T06:49:11Z
Language en_AU
Research Centre Griffith Health Institute; Molecular Basis of Disease
Faculty Griffith Health Faculty
Subject Cancer Cell Biology
URI http://hdl.handle.net/10072/34071
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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