Document Detail


Oestrogen-related receptor alpha inverse agonist XCT-790 arrests A549 lung cancer cell population growth by inducing mitochondrial reactive oxygen species production.
MedLine Citation:
PMID:  20447055     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Although oestrogen-related receptor alpha (ERRalpha) is primarily thought to regulate energy homeostasis, it also serves as a prognostic marker for cancer. The aim of this study was to investigate any connection between ERRalpha activity and cell population growth. MATERIALS AND METHODS: XCT-790, an ERRa specific inverse agonist, was employed to suppress ERRa activity in human non-small cell lung cancer cells (NSCLC) A549. Gene expressions were detected using quantitative real-time PCR and Western blot analysis. Mitochondrial mass, membrane potential and reactive oxygen species (ROS) production were measured by staining with Mitotracker green, JC-1 and CM-H(2)DCFDA dyes respectively. Rate of progression through the tricarboxylic acid (TCA) cycle was analysed by measuring activities of citrate synthase and succinate dehydrogenase. Cell cycle analysis was performed by using flow cytometry. RESULTS: We found that XCT-790 treatment reduced mitochondrial mass but enhanced mitochondrial ROS production by increasing rate through the TCA cycle, elevating mitochondrial membrane potential (DeltaPsi(m)) and down-regulating expression of superoxide dismutase. It was further demonstrated that XCT-790-induced ROS modulated p53 and Rb signalling pathways and suppressed cell replication. CONCLUSIONS: ERRalpha affects cell cycle mechanisms through modulating mitochondrial mass and function. Dysregulation of this essential pathway leads to elevation in mitochondrial ROS production, which in turn modulates activities of tumour suppressors, resulting in cell cycle arrest.
Authors:
J Wang; Y Wang; C Wong
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell proliferation     Volume:  43     ISSN:  1365-2184     ISO Abbreviation:  Cell Prolif.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-05-07     Completed Date:  2010-06-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9105195     Medline TA:  Cell Prolif     Country:  England    
Other Details:
Languages:  eng     Pagination:  103-13     Citation Subset:  IM    
Affiliation:
Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
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MeSH Terms
Descriptor/Qualifier:
Benzimidazoles / metabolism
Carbocyanines / metabolism
Carcinoma, Non-Small-Cell Lung / metabolism*,  pathology
Cell Cycle
Cell Line, Tumor
Dose-Response Relationship, Drug
Fluorescent Dyes / metabolism
Humans
Lung / metabolism,  pathology
Lung Neoplasms / metabolism*,  pathology
Membrane Potential, Mitochondrial / drug effects
Membrane Potentials / drug effects
Mitochondria / drug effects
Nitriles / pharmacology*
Reactive Oxygen Species / analysis,  metabolism*
Receptors, Estrogen / agonists*
Signal Transduction / drug effects
Superoxide Dismutase / metabolism
Thiazoles / pharmacology*
Time Factors
Tumor Suppressor Protein p53 / metabolism
Chemical
Reg. No./Substance:
0/Benzimidazoles; 0/Carbocyanines; 0/ERRalpha estrogen-related receptor; 0/Fluorescent Dyes; 0/Nitriles; 0/Reactive Oxygen Species; 0/Receptors, Estrogen; 0/Thiazoles; 0/Tumor Suppressor Protein p53; 0/XCT790; 21527-78-6/5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; EC 1.15.1.1/Superoxide Dismutase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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