Document Detail

Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells.
MedLine Citation:
PMID:  23018647     Owner:  NLM     Status:  MEDLINE    
Malignant mesothelioma (MM) is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure to asbestos. Recently, we described an interplay between mitochondrial-derived oxidants and expression of FOXM1, a redox-responsive transcription factor that has emerged as a promising therapeutic target in solid malignancies. Here we have investigated the effects of nitroxides targeted to mitochondria via triphenylphosphonium (TPP) moieties on mitochondrial oxidant production, expression of FOXM1 and peroxiredoxin 3 (PRX3), and cell viability in MM cells in culture. Both Mito-carboxy-proxyl (MCP) and Mito-TEMPOL (MT) caused dose-dependent increases in mitochondrial oxidant production that was accompanied by inhibition of expression of FOXM1 and PRX3 and loss of cell viability. At equivalent concentrations TPP, CP, and TEMPOL had no effect on these endpoints. Live cell ratiometric imaging with a redox-responsive green fluorescent protein targeted to mitochondria (mito-roGFP) showed that MCP and MT, but not CP, TEMPOL, or TPP, rapidly induced mitochondrial fragmentation and swelling, morphological transitions that were associated with diminished ATP levels and increased production of mitochondrial oxidants. Mdivi-1, an inhibitor of mitochondrial fission, did not rescue mitochondria from fragmentation by MCP. Immunofluorescence microscopy experiments indicate a fraction of FOXM1 coexists in the cytoplasm with mitochondrial PRX3. Our results indicate that MCP and MT inhibit FOXM1 expression and MM tumor cell viability via perturbations in redox homeostasis caused by marked disruption of mitochondrial architecture, and suggest that both compounds, either alone or in combination with thiostrepton or other agents, may provide credible therapeutic options for the management of MM.
Brian Cunniff; Kira Benson; Jason Stumpff; Kheng Newick; Paul Held; Douglas Taatjes; Joy Joseph; Balaraman Kalyanaraman; Nicholas H Heintz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  228     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-01-02     Completed Date:  2013-05-22     Revised Date:  2014-02-25    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  835-45     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
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MeSH Terms
Adenosine Triphosphate / metabolism
Cell Line, Tumor
Cell Survival / drug effects,  genetics
Cytoplasm / drug effects,  genetics,  metabolism,  physiology
Forkhead Transcription Factors / antagonists & inhibitors*,  biosynthesis*,  genetics,  metabolism
Homeostasis / drug effects,  genetics,  physiology
Mesothelioma / metabolism*,  pathology
Mitochondria / drug effects,  metabolism*
Mitochondrial Dynamics / drug effects,  genetics,  physiology
Organophosphorus Compounds / pharmacology
Oxidants / metabolism*
Oxidation-Reduction / drug effects
Peroxiredoxin III / antagonists & inhibitors*,  biosynthesis*,  genetics,  metabolism
Quinazolinones / pharmacology
Grant Support
R01 CA152810/CA/NCI NIH HHS; T32 ES007122/ES/NIEHS NIH HHS; T32 ES007122-29/ES/NIEHS NIH HHS
Reg. No./Substance:
0/3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; 0/FOXM1 protein, human; 0/Forkhead Transcription Factors; 0/Organophosphorus Compounds; 0/Oxidants; 0/Quinazolinones; 0/triphenylphosphonium methylide; 8L70Q75FXE/Adenosine Triphosphate; EC protein, human; EC III

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