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Lactate promotes glutamine uptake and metabolism in oxidative cancer cells
Open accessAbstract
Oxygenated cancer cells have a high metabolic plasticity as they can use glucose, glutamine and lactate as main substrates to support their bioenergetic and biosynthetic activities. Metabolic optimization requires integration. While glycolysis and glutaminolysis can cooperate to support cellular proliferation, oxidative lactate metabolism opposes glycolysis in oxidative cancer cells engaged in a symbiotic relation with their hypoxic/glycolytic neighbors. However, little is known concerning the relationship between oxidative lactate metabolism and glutamine metabolism. Using SiHa and HeLa human cancer cells, this study reports that intracellular lactate signaling promotes glutamine uptake and metabolism in oxidative cancer cells. It depends on the uptake of extracellular lactate by monocarboxylate transporter 1 (MCT1). Lactate first stabilizes hypoxia-inducible factor-2α (HIF-2α), and HIF-2α then transactivates c-Myc in a pathway that mimics a response to hypoxia. Consequently, lactate-induced c-Myc activation triggers the expression of glutamine transporter ASCT2 and of glutaminase 1 (GLS1), resulting in improved glutamine uptake and catabolism. Elucidation of this metabolic dependence could be of therapeutic interest. First, inhibitors of lactate uptake targeting MCT1 are currently entering clinical trials. They have the potential to indirectly repress glutaminolysis. Second, in oxidative cancer cells, resistance to glutaminolysis inhibition could arise from compensation by oxidative lactate metabolism and increased lactate signaling.
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“It has long been established that Myc activation upregulates glutamine metabolism [79,80], increasing glutamine flux by upregulating the glutamine transporter (ASCT2) and glutaminase-1, thus increasing glutamine conversion to glutamate [81].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [81]
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“In addition, extracellular lactate stabilizes HIF-2α, and HIF-2α then transactivates MYC, increasing the levels of glutamine transporters and GLS1, in turn resulting in increased glutamine catabolism72.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [72]
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Buck, M. D., Sowell, R., Kaech, S. M., & Pearce, E. L. (2017) · Cell · doi:10.1016/j.cell.2017.04.004 · Cited by 1,270
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021
Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches
de la Cruz-López, K. G., Castro-Muñoz, L. J., Reyes-Hernández, D. O., García-Carrancá, A., & Manzo-Merino, J. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01143 · Cited by 940
“Lactate-induced c-MYC activation triggers the expression of the glutamine transporter ASCT2 and glutaminase 1 (GLS1), both resulting in improved glutamine uptake and catabolism (59).”
Background
Metadata
- Authors
- Pérez-Escuredo, J., Dadhich, R. K., Dhup, S., Cacace, A., Van Hée, V. F., De Saedeleer, C. J., Sboarina, M., Rodriguez, F., Fontenille, M.-J., Brisson, L., Porporato, P. E., & Sonveaux, P.
- Affiliations
- From the Pole of Pharmacology, Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCL) Medical School, Brussels, Belgium
- UCLouvain (BE)
- Corresponding author
- Sonveaux, Pierre
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2016-01-02
- Volume
- 15
- Issue
- 1
- Pages
- 72-83
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC4825768
- OpenAlex
- W2184384535
- Cited by
- 231
- References
- 56
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 27 · 2023: 24 · 2022: 22 · 2021: 27 · 2020: 29 · 2019: 19 · 2018: 11 · 2017: 22 · 2016: 9
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Digital Access to Libraries (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Fonds De La Recherche Scientifique - FNRS
- Belgian Federal Science Policy Office (UP7-03)
- Fonds Joseph Maisin
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- lactate metabolism, glutamine uptake, glutaminolysis, MCT1, HIF-2α, c-Myc, ASCT2, GLS1, cancer metabolism, metabolic plasticity, lactate signaling, glycolysis
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Monocarboxylate Transport Protein 1, Animals, Glutaminase, Glutamine, HeLa Cells, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Oxidation-Reduction, Lactic Acid, Monocarboxylic Acid Transporters, Symporters, Mice, Basic Helix-Loop-Helix Proteins
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