Document Detail


Mitochondrial uncoupling inhibits p53 mitochondrial translocation in TPA-challenged skin epidermal JB6 cells.
MedLine Citation:
PMID:  20976134     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The tumor suppressor p53 is known to be able to trigger apoptosis in response to DNA damage, oncogene activation, and certain chemotherapeutic drugs. In addition to its transcriptional activation, a fraction of p53 translocates to mitochondria at the very early stage of apoptosis, which eventually contributes to the loss of mitochondrial membrane potential, generation of reactive oxygen species (ROS), cytochrome c release, and caspase activation. However, the mitochondrial events that affect p53 translocation are still unclear. Since mitochondrial uncoupling has been suggested to contribute to cancer development, herein, we studied whether p53 mitochondrial translocation and subsequent apoptosis were affected by mitochondrial uncoupling using chemical protonophores, and further verified the results using a siRNA approach in murine skin epidermal JB6 cells. Our results showed that mitochondrial uncoupling blocked p53 mitochondrial translocation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA), a known tumor promoter to induce p53-mediated apoptosis in skin carcinogenesis. This blocking effect, in turn, led to preservation of mitochondrial functions, and eventually suppression of caspase activity and apoptosis. Moreover, uncoupling protein 2 (UCP2), a potential suppressor of ROS in mitochondria, is important for TPA-induced cell transformation in JB6 cells. UCP2 knock down cells showed enhanced p53 mitochondrial translocation, and were less prone to form colonies in soft agar after TPA treatment. Altogether, our data suggest that mitochondrial uncoupling may serve as an important regulator of p53 mitochondrial translocation and p53-mediated apoptosis during early tumor promotion. Therefore, targeting mitochondrial uncoupling may be considered as a novel treatment strategy for cancer.
Authors:
Fei Wang; Xueqi Fu; Xia Chen; Xinbin Chen; Yunfeng Zhao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-18
Journal Detail:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-10-26     Completed Date:  2011-03-07     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e13459     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Blotting, Western
Cell Line
Fluorescent Antibody Technique
Membrane Potentials
Mice
Mitochondria / drug effects*,  metabolism,  physiology
Skin / cytology,  drug effects*,  metabolism
Tetradecanoylphorbol Acetate / pharmacology*
Tumor Suppressor Protein p53 / metabolism*
Grant Support
ID/Acronym/Agency:
R03CA128077/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Tumor Suppressor Protein p53; 16561-29-8/Tetradecanoylphorbol Acetate
Comments/Corrections

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