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ToxSci Advance Access originally published online on May 18, 2009
Toxicological Sciences 2009 110(2):376-388; doi:10.1093/toxsci/kfp101
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Oxidative Stress Induces Parallel Autophagy and Mitochondria Dysfunction in Human Glioma U251 Cells

Hongyu Zhang1, Xiaoxia Kong1, Jinsong Kang, Jing Su, Yang Li, Jiateng Zhong and Liankun Sun2

Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China

2 To whom correspondence should be addressed at Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, 2 Xinmin Street, Changchun, Jilin 130021, China. Fax: +86-431-85619402. E-mail: sunlk{at}jlu.edu.cn.

Received February 14, 2009; accepted May 8, 2009


  Abstract

Accumulation of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) is an oxidative stress response, which induced various defense mechanisms or programmed cell death (PCD). As one of the major types of PCD, autophagy has been observed in response to several anticancer drugs and demonstrated to be responsible for cell death. To date, however, the exact mechanism by which ROS regulates autophagy is still poorly understood. Thus, the purposes of this study were to elucidate how H2O2 exerts its cytotoxic effects on malignant glioma U251 cells and to uncover the molecular mechanism that might be involved. Here, we show that H2O2-induced autophagy and apoptosis in U251 cells are mediated through the Beclin 1 and Akt/mTOR pathways. Accumulation of ROS leads to changes in mitochondrial permeability with loss of mitochondrial membrane potential and disruption of mitochondrial dynamics at a transcriptional level of fission and fusion. Overexpression of cellular Bcl-2 partially inhibited autophagy through both the Beclin 1 and the Akt/mTOR pathways and led to recovery of mitochondrial dynamics. When autophagy was prevented at an early stage by 3-methyladenine, apoptosis significantly increased. Our data provide the first evidence that H2O2 induces autophagy through interference with the Beclin 1 and Akt/mTOR signaling pathways and is regulated by the anti-apoptotic gene Bcl-2 in glioma U251 cells.

Key Words: autophagy; mitochondria; Bcl-2; PI3K/Akt/mTOR; apoptosis.

1 These authors contributed equally to this study.


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