Cited by 168Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerMitochondrial Function and Pathology

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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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Samudio, Ismael, Fiegl, Michael, McQueen, Teresa, Clise-Dwyer, Karen, Andreeff, Michael·2008·Cancer Research

DOI 10.1158/0008-5472.can-08-0555PMC PMC2562568

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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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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)
ORCID: Samudio, Ismael
McQueen, Teresa
Clise-Dwyer, Karen
Andreeff, Michael
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2008-07-01
Volume: 68
Issue: 13
Pages: 5198-5205
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-08-0555
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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The Warburg Effect in Leukemia-Stroma Cocultures Is Mediated by Mitochondrial Uncoupling Associated with Uncoupling Protein 2 Activation

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