Skip Navigation



Carcinogenesis Advance Access published online on June 9, 2008
Carcinogenesis, doi:10.1093/carcin/bgn137
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
29/8/1538    most recent
bgn137v2
bgn137v1
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 Azad, N.
Right arrow Articles by Rojanasakul, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Azad, N.
Right arrow Articles by Rojanasakul, Y.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Superoxide-Mediated Proteasomal Degradation of Bcl-2 Determines Cell Susceptibility to Cr(VI)-Induced Apoptosis

Neelam Azad{dagger},||, V. Iyer Anand Krishnan{dagger}, Aranya Manosroi{ddagger}, Liying Wang§ and Yon Rojanasakul{dagger}

{dagger} Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506
{ddagger} Department of Pharmaceutical Sciences, Chiangmai University, Chiangmai 50200, Thailand
§ Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV 26505

|| To whom correspondence should be addressed: Neelam Azad, Ph.D., Department of Pharmaceutical Sciences, West Virginia University, P.O. Box 9530, Morgantown, WV 26506. Email: nazad{at}hsc.wvu.edu

Hexavalent chromium [Cr(VI)] compounds are redox cycling environmental carcinogens that induce apoptosis as the primary mode of cell death. Defects in apoptosis regulatory mechanisms contributes to carcinogenesis induced by Cr(VI). Activation of apoptosis signaling pathways is tightly linked with the generation of reactive oxygen species (ROS). Likewise, ROS have been implicated in the regulation of Cr(VI)-induced apoptosis and carcinogenicity; however, its role in Cr(VI)-induced apoptosis and the underlying mechanism are largely unknown. We report that ROS, specifically superoxide anion (·OFormula) mediates Cr(VI)-induced apoptosis of human lung epithelial H460 cells. H460 {rho}0 cells that lack mitochondrial DNA demonstrated a significant decrease in ROS production and apoptotic response to Cr(VI), indicating the involvement of mitochondrial ROS in Cr(VI)-induced apoptosis. In agreement with this observation, we found that Cr(VI) induces apoptosis mainly through the mitochondrial death pathway via caspase-9 activation, which is negatively regulated by the anti-apoptotic protein Bcl-2. Furthermore, ·OFormula induced apoptosis in response to Cr(VI) exposure by down-regulating and degrading Bcl-2 protein through the ubiquitin-proteasomal pathway. This study reveals a novel mechanism linking ·OFormula with Bcl-2 stability and provides a new dimension to ROS-mediated Bcl-2 downregulation and apoptosis induction.

Key Words: Cr(VI) • apoptosis • superoxide • Bcl-2 • ubiquitination

Received February 18, 2008; revised April 26, 2008; accepted May 26, 2008.


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




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.