Document Detail

The warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation.
MedLine Citation:
PMID:  18593920     Owner:  NLM     Status:  MEDLINE    
In 1956, Otto Warburg proposed that the origin of cancer cells was closely linked to a permanent respiratory defect that bypassed the Pasteur effect (i.e., the inhibition of anaerobic fermentation by oxygen). Since then, permanent defects in oxygen consumption that could explain the dependence of cancer cells on aerobic glycolysis have not been identified. Here, we show that under normoxic conditions exposure of leukemia cells to bone marrow-derived mesenchymal stromal cells (MSC) promotes accumulation of lactate in the culture medium and reduces mitochondrial membrane potential (DeltaPsiM) in both cell types. Notably, the consumption of glucose was not altered in cocultures, suggesting that the accumulation of lactate was the result of reduced pyruvate metabolism. Interestingly, the decrease in DeltaPsiM was mediated by mitochondrial uncoupling in leukemia cells and was accompanied by increased expression of uncoupling protein 2 (UCP2). HL60 cells fail to increase UCP2 expression, are not uncoupled after coculture, and do not exhibit increased aerobic glycolysis, whereas small interfering RNA-mediated suppression of UCP2 in OCI-AML3 cells reversed mitochondrial uncoupling and aerobic glycolysis elicited by MSC. Taken together, these data suggest that microenvironment activation of highly conserved mammalian UCPs may facilitate the Warburg effect in the absence of permanent respiratory impairment.
Ismael Samudio; Michael Fiegl; Teresa McQueen; Karen Clise-Dwyer; Michael Andreeff
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  68     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-07-02     Completed Date:  2008-08-05     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5198-205     Citation Subset:  IM    
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MeSH Terms
Aerobiosis / physiology
Bone Marrow Cells / drug effects,  metabolism
Cells, Cultured
Coculture Techniques
Culture Media, Conditioned / metabolism,  pharmacology*
Glycolysis / drug effects
HL-60 Cells
Ion Channels / metabolism*,  physiology*
Leukemia / metabolism*
Membrane Potential, Mitochondrial / drug effects
Mesenchymal Stromal Cells / drug effects,  metabolism
Mitochondria / drug effects,  metabolism*
Mitochondrial Proteins / metabolism*,  physiology*
Stromal Cells / drug effects*,  metabolism
Uncoupling Agents / metabolism,  pharmacology
Grant Support
P01 CA055164/CA/NCI NIH HHS; P01 CA055164-060010/CA/NCI NIH HHS; P01 CA055164-069006/CA/NCI NIH HHS; P01 CA055164-070010/CA/NCI NIH HHS; P01 CA055164-079006/CA/NCI NIH HHS; P01 CA55164/CA/NCI NIH HHS
Reg. No./Substance:
0/Culture Media, Conditioned; 0/Ion Channels; 0/Mitochondrial Proteins; 0/Uncoupling Agents; 0/mitochondrial uncoupling protein 2

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