The warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation

Ismael Samudio, Michael Fiegl, Teresa McQueen, Karen Clise-Dwyer, Michael Andreeff

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

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 (ΔΨM) 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 ΔΨM 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.

Original languageEnglish (US)
Pages (from-to)5198-5205
Number of pages8
JournalCancer research
Volume68
Issue number13
DOIs
StatePublished - Jul 1 2008

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Coculture Techniques
Leukemia
Glycolysis
Mesenchymal Stromal Cells
Lactic Acid
Mitochondrial Membrane Potential
HL-60 Cells
Pyruvic Acid
Oxygen Consumption
Bone Marrow Cells
Small Interfering RNA
Fermentation
Culture Media
Neoplasms
Uncoupling Protein 2
Oxygen
Glucose

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. / Samudio, Ismael; Fiegl, Michael; McQueen, Teresa; Clise-Dwyer, Karen; Andreeff, Michael.

In: Cancer research, Vol. 68, No. 13, 01.07.2008, p. 5198-5205.

Research output: Contribution to journalArticle

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