Document Detail

Reactive oxygen species regulate Bax translocation and mitochondrial transmembrane potential, a possible mechanism for enhanced TRAIL-induced apoptosis by CCCP.
MedLine Citation:
PMID:  17549348     Owner:  NLM     Status:  MEDLINE    
TRAIL is a TNF family member that engages apoptosis via recruitment and rapid activation of caspase-8. Oxygen-free radicals, more generally known as reactive oxygen species (ROS) are well recognized for playing an important role in the regulation of tumor cell apoptosis. ROS within the cells act as secondary messengers in intracellular signalling cascades therefore function as anti-tumorigenic species. But very little is known about the effect of ROS on TRAIL-induced apoptosis. In this study we investigated the effect of CCCP, a classic uncoupler of oxidative phosphorylation, on TRAIL-induced apoptosis in TRAIL-resistant MCF-7 cells. It was found that pretreatment with CCCP for 6 h and then treatment with TRAIL for additional 3 h markedly enhanced apoptosis by 2-fold as compared with TRAIL alone. The uncoupling effect enhanced TRAIL-induced apoptosis by ROS generation. Moreover, CCCP treatment also reduced mitochondrial transmembrane potential (MTP, Delta Psi m) and induced Bax translocation to the mitochondria of its own account. This sensitization was inhibited with N-acetyl-L-cysteine (NAC) treatment by abrogating the ROS which was generated by the combined treatment of CCCP and TRAIL. Of interest, NAC also inhibited reduction of the Delta Psi m and Bax translocation after CCCP pretreatment which suggest that the generation of ROS may precede the loss in MTP. Thus, we demonstrated that CCCP-induced ROS generation enhanced TRAIL induced apoptosis by regulation of Bax translocation and mitochondrial transmembrane potential. The enhancing effect by CCCP-induced ROS generation was restored after NAC treatment. Therefore, our results suggest that uncoupling the cells by CCCP can overcome the resistance to TRAIL protein and can be a very efficient treatment for the tumor cells especially resistant to TRAIL-induced apoptosis.
Atul A Chaudhari; Jae-Won Seol; Shang-Jin Kim; You-Jin Lee; Hyung-Sub Kang; In-Shik Kim; Nam-Soo Kim; Sang-Youel Park
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncology reports     Volume:  18     ISSN:  1021-335X     ISO Abbreviation:  Oncol. Rep.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-06-05     Completed Date:  2007-08-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9422756     Medline TA:  Oncol Rep     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  71-6     Citation Subset:  IM    
Center for Healthcare Technology Development, Bio-Safty Research Institute College of Veterinary Medicine, Chonbuk National University, Jeonbuk 561-756, South Korea.
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MeSH Terms
Adenocarcinoma / metabolism,  pathology
Apoptosis / drug effects*
Blotting, Western
Breast Neoplasms / metabolism,  pathology
Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology*
Caspases / metabolism
Membrane Potential, Mitochondrial / drug effects*
Protein Transport
Reactive Oxygen Species / metabolism*
TNF-Related Apoptosis-Inducing Ligand / pharmacology*
Tumor Cells, Cultured
Uncoupling Agents / pharmacology*
bcl-2-Associated X Protein / metabolism*
Reg. No./Substance:
0/BAX protein, human; 0/Reactive Oxygen Species; 0/TNF-Related Apoptosis-Inducing Ligand; 0/Uncoupling Agents; 0/bcl-2-Associated X Protein; 555-60-2/Carbonyl Cyanide m-Chlorophenyl Hydrazone; EC 3.4.22.-/Caspases

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