Document Detail


Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-RAS(Q61L).
MedLine Citation:
PMID:  19923925     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A common metabolic change in cancer is the acquisition of glycolytic phenotypes. Increased expression of glycolytic enzymes is considered as one contributing factor. The role of mitochondrial defects in acquisition of glycolytic phenotypes has been postulated but remains controversial. Here we show that functional defects in mitochondrial respiration could be induced by oncogenic H-Ras(Q61L) transformation, even though the mitochondrial contents or mass was not reduced in the transformed cells. First, mitochondrial respiration, as measured by mitochondrial oxygen consumption, was suppressed in NIH-3T3 cells transformed with H-Ras(Q61L). Second, oligomycin or rotenone did not reduce the cellular ATP levels in the H-Ras(Q61L) transformed cells, suggesting a diminished role of mitochondrial respiration in the cellular energy metabolism. Third, inhibition of glycolysis with iodoacetic acid reduced ATP levels at a much faster rate in H-Ras(Q61L) transformed cells than in the vector control cells. The reduction of cellular ATP levels was reversed by exogenously added pyruvate in the vector control cells but not in H-Ras(Q61L) transformed cells. Finally when compared to the HRas(Q61L) transformed cells, the vector control cells had increased resistance toward glucose deprivation. The increased resistance was dependent on mitochondrial oxidative phosphorylation since rotenone or oligomycin abolished the increased survival of the vector control cells under glucose deprivation. The results also suggest an inability of the H-Ras(Q61L) transformed cells to reactivate mitochondrial respiration under glucose deprivation. Taken together, the data suggest that mitochondrial respiration can be impaired during transformation of NIH-3T3 cells by oncogeneic H-Ras(Q61L).
Authors:
Dianer Yang; Man-Tzu Wang; Yong Tang; Yakun Chen; Hongmei Jiang; Torrie T Jones; Krishna Rao; Gregory J Brewer; Keshav K Singh; Daotai Nie
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-01-21
Journal Detail:
Title:  Cancer biology & therapy     Volume:  9     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-04-13     Completed Date:  2010-08-25     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  122-33     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Animals
Antimycin A / pharmacology
Cell Transformation, Neoplastic*
Electron Transport / drug effects
Energy Metabolism / drug effects
Fibroblasts / metabolism*
Genes, ras*
Glucose / metabolism
Glycolysis / drug effects
Iodoacetic Acid / pharmacology
Mice
Mitochondria / drug effects,  metabolism*
Mutation, Missense
NIH 3T3 Cells / metabolism
Oligomycins / pharmacology
Oncogene Protein p21(ras) / genetics,  physiology*
Oxidative Phosphorylation / drug effects
Oxygen Consumption / drug effects
Point Mutation
Pyruvic Acid / pharmacology
Rotenone / pharmacology
Grant Support
ID/Acronym/Agency:
R01 CA121904/CA/NCI NIH HHS; R01 CA121904-10/CA/NCI NIH HHS; R01 CA121904-11/CA/NCI NIH HHS; R01AG013435/AG/NIA NIH HHS; R01CA121904/CA/NCI NIH HHS; R01CA131445/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Oligomycins; 03L9OT429T/Rotenone; 642-15-9/Antimycin A; 8558G7RUTR/Pyruvic Acid; 8L70Q75FXE/Adenosine Triphosphate; EC 3.6.5.2/Oncogene Protein p21(ras); IY9XDZ35W2/Glucose; WF5188V710/Iodoacetic Acid
Comments/Corrections

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


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