The warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation.
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.
Samudio
Ismael
I
Department of Stem Cell Transplantation and Cellular Therapy, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Fiegl
Michael
M
McQueen
Teresa
T
Clise-Dwyer
Karen
K
Andreeff
Michael
M
D000332:Aerobiosis / Q000502:physiology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism* / Q000502:physiology*; D007938:Leukemia / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism* / Q000502:physiology*; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism; D014475:Uncoupling Agents / Q000378:metabolism / Q000494:pharmacology; D000071246:Uncoupling Protein 2
D017077:Culture Media, Conditioned; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604389:UCP2 protein, human; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2