Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice
Pierre Sonveaux,Frédérique Végran,Thies Schroeder,Melanie Wergin,Julien Verrax,Zahid N. Rabbani,Christophe De Saedeleer,Kelly M. Kennedy,Caroline Diepart,Bénédicte F. Jordan,Michael J. Kelley,Bernard Gallez,Miriam L. Wahl,Olivier Feron,Mark W. Dewhirst +14 more
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In this paper, the authors identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism.Abstract:
Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with alpha-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential.read more
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Otto Warburg's contributions to current concepts of cancer metabolism
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References
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Michael P. King,Giuseppe Attardi +1 more
TL;DR: Transformants obtained with various mitochondrial donors exhibited a respiratory phenotype that was in most cases distinct from that of the rho 0 parent or the donor, indicating that the genotypes of the mitochondrial and nuclear genomes as well as their specific interactions play a role in the respiratory competence of a cell.
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The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation
TL;DR: There is still much work to be done to characterize the properties of the different MCT isoforms and their regulation, which may have wide-ranging implications for health and disease.
Journal ArticleDOI
Cancer's Molecular Sweet Tooth and the Warburg Effect
Jung Whan Kim,Chi V. Dang +1 more
TL;DR: Molecular advances in this area may reveal tactics to exploit the cancer cell's "sweet tooth" for cancer therapy and renewed discussions about its exact role as cause, correlate, or facilitator of cancer.