Skip Navigation



Carcinogenesis Advance Access published online on August 14, 2007
Carcinogenesis, doi:10.1093/carcin/bgm143
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
28/9/1937    most recent
bgm143v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lu, G. D.
Right arrow Articles by Ong, C. N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lu, G. D.
Right arrow Articles by Ong, C. N.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Critical Role of Oxidative Stress and Sustained JNK Activation in Aloe-Emodin-Mediated Apoptotic Cell Death in Human Hepatoma Cells

Guo Dong Lu1,2, Han-Ming Shen2, Maxey C.M. Chung1,3 and Choon Nam Ong2,4,*

1 Department of Biochemistry
2 Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine
3 Department of Biological Sciences, Faculty of Science
4 Office of Life Sciences, National University of Singapore, Singapore

* To whom correspondence should be addressed: Tel:6516-4982, Fax: 6779-1489. Email: cofongcn{at}nus.edu.sg

Aloe-emodin (AE), one of the main bioactive anthraquinones of Rheum palmatum, possesses potent anti-tumor properties. Our previous proteomic study revealed that AE-induced apoptosis was associated with oxidative stress and oxidation of many redox-sensitive proteins. In this study we aimed to further dissect the cell death signaling pathways in AE-induced apoptosis. AE was found to cause redox imbalance and deplete the intracellular reduced glutathione (GSH). Manipulation of the intracellular GSH with buthionine-L-sulfoxinine (BSO, a GSH synthesis inhibitor) sensitized, and with GSH-MEE (a GSH donor) protected the AE-induced apoptosis, respectively. More importantly, AE treatment led to evident and sustained activation of c-Jun N-terminal kinase (JNK), an important stress-responsive mitogen activated protein kinase (MAPK). Over-expression of antioxidant gene sod1 significantly reduced AE-induced JNK activation and cell death, suggesting that oxidative stress-mediated JNK is the effector molecule in AE-induced apoptosis. Such a notion was clearly supported by subsequent studies in which JNK activation was inhibited by JNK inhibitor, JNK siRNA knockdown or over-expression of dominant negative JNK. In addition, we provided evidence demonstrating the critical role of apoptosis signal-regulating kinase1 (ASK1), a well established MAPK kinase kinase, in AE-induced JNK activation and apoptotic cell death. Finally, we showed that dissociation of inactive JNK-GST-pi complex was also involved in JNK activation through GST-pi oxidation. Taken together, these results suggest that AE-induced apoptotic cell death is mediated via oxidative stress and sustained JNK activation.

Key Words: Liver cancer • herbal • anthroquinone • glutathione • mitogen activated protein kinase

Received March 9, 2007; revised May 14, 2007; accepted June 11, 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Molecular Cancer TherapeuticsHome page
J. Zhou, G.-D. Lu, C.-S. Ong, C.-N. Ong, and H.-M. Shen
Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation
Mol. Cancer Ther., July 1, 2008; 7(7): 2170 - 2180.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.