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The Warburg Effect in Leukemia-Stroma Cocultures Is Mediated by Mitochondrial Uncoupling Associated with Uncoupling Protein 2 Activation
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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 (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.
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“the critical role of UCP2 (uncoupling protein 2) in promoting aerobic glycolysis and inhibiting oxidative phosphorylation has been established from multiple experimental models (Pecqueur et al., 2008; Samudio et al., 2008; Bouillaud, 2009; Zhang et al., 2011).”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Samudio et al., 2008
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“In addition to the conventional regulators of glycolysis, TCA and oxidative phosphorylation, the critical role of UCP2 (uncoupling protein 2) in promoting aerobic glycolysis and inhibiting oxidative phosphorylation has been established from multiple experimental models (Pecqueur et al., 2008; Samudio et al., 2008; Bou…”
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Zhang, J., Khvorostov, I., Hong, J. S., Oktay, Y., Vergnes, L., Nuebel, E., Wahjudi, P. N., Setoguchi, K., Wang, G., Do, A., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.401 · Cited by 512
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Metadata
- Authors
- Samudio, I., Fiegl, M., McQueen, T., Clise-Dwyer, K., & Andreeff, M.
- Affiliations
- 1Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, and
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Cancer Research
- Published
- 2008-07-01
- Volume
- 68
- Issue
- 13
- Pages
- 5198-5205
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2562568
- OpenAlex
- W2032999577
- Cited by
- 168
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 17 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 5 · 2016: 14 · 2015: 10 · 2014: 20 · 2013: 14 · 2012: 12
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01 CA-55164, P01CA055164)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Warburg effect, leukemia, mesenchymal stem cells, mitochondrial uncoupling, UCP2, aerobic glycolysis, mitochondrial membrane potential, lactate accumulation, pyruvate metabolism, bone marrow microenvironment, HL-60 cells, OCI-AML3 cells, oxygen consumption
- MeSH terms
- Uncoupling Protein 2, Aerobiosis, Bone Marrow Cells, Cells, Cultured, Glycolysis, Humans, Ion Channels, Leukemia, Mitochondria, Uncoupling Agents, Culture Media, Conditioned, Stromal Cells, Coculture Techniques, HL-60 Cells, Mitochondrial Proteins, Membrane Potential, Mitochondrial, Mesenchymal Stem Cells
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