Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.

Cancer can be envisioned as a metabolic disease driven by pressure selection and intercellular cooperativeness. Together with anaerobic glycolysis, the Warburg effect, formally corresponding to uncoupling glycolysis from oxidative phosphorylation, directly participates in cancer aggressiveness, supp...

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Autores principales:	Christophe J De Saedeleer, Tamara Copetti, Paolo E Porporato, Julien Verrax, Olivier Feron, Pierre Sonveaux
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9863463c24784addba273d7388d4e2f9
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spelling	oai:doaj.org-article:9863463c24784addba273d7388d4e2f92021-11-18T08:11:45ZLactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.1932-620310.1371/journal.pone.0046571https://doaj.org/article/9863463c24784addba273d7388d4e2f92012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23082126/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Cancer can be envisioned as a metabolic disease driven by pressure selection and intercellular cooperativeness. Together with anaerobic glycolysis, the Warburg effect, formally corresponding to uncoupling glycolysis from oxidative phosphorylation, directly participates in cancer aggressiveness, supporting both tumor progression and dissemination. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key contributor to glycolysis. It stimulates the expression of glycolytic transporters and enzymes supporting high rate of glycolysis. In this study, we addressed the reverse possibility of a metabolic control of HIF-1 in tumor cells. We report that lactate, the end-product of glycolysis, inhibits prolylhydroxylase 2 activity and activates HIF-1 in normoxic oxidative tumor cells but not in Warburg-phenotype tumor cells which also expressed lower basal levels of HIF-1α. These data were confirmed using genotypically matched oxidative and mitochondria-depleted glycolytic tumor cells as well as several different wild-type human tumor cell lines of either metabolic phenotype. Lactate activates HIF-1 and triggers tumor angiogenesis and tumor growth in vivo, an activity that we found to be under the specific upstream control of the lactate transporter monocarboxylate transporter 1 (MCT1) expressed in tumor cells. Because MCT1 also gates lactate-fueled tumor cell respiration and mediates pro-angiogenic lactate signaling in endothelial cells, MCT1 inhibition is confirmed as an attractive anticancer strategy in which a single drug may target multiple tumor-promoting pathways.Christophe J De SaedeleerTamara CopettiPaolo E PorporatoJulien VerraxOlivier FeronPierre SonveauxPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e46571 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christophe J De Saedeleer Tamara Copetti Paolo E Porporato Julien Verrax Olivier Feron Pierre Sonveaux Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.
description	Cancer can be envisioned as a metabolic disease driven by pressure selection and intercellular cooperativeness. Together with anaerobic glycolysis, the Warburg effect, formally corresponding to uncoupling glycolysis from oxidative phosphorylation, directly participates in cancer aggressiveness, supporting both tumor progression and dissemination. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key contributor to glycolysis. It stimulates the expression of glycolytic transporters and enzymes supporting high rate of glycolysis. In this study, we addressed the reverse possibility of a metabolic control of HIF-1 in tumor cells. We report that lactate, the end-product of glycolysis, inhibits prolylhydroxylase 2 activity and activates HIF-1 in normoxic oxidative tumor cells but not in Warburg-phenotype tumor cells which also expressed lower basal levels of HIF-1α. These data were confirmed using genotypically matched oxidative and mitochondria-depleted glycolytic tumor cells as well as several different wild-type human tumor cell lines of either metabolic phenotype. Lactate activates HIF-1 and triggers tumor angiogenesis and tumor growth in vivo, an activity that we found to be under the specific upstream control of the lactate transporter monocarboxylate transporter 1 (MCT1) expressed in tumor cells. Because MCT1 also gates lactate-fueled tumor cell respiration and mediates pro-angiogenic lactate signaling in endothelial cells, MCT1 inhibition is confirmed as an attractive anticancer strategy in which a single drug may target multiple tumor-promoting pathways.
format	article
author	Christophe J De Saedeleer Tamara Copetti Paolo E Porporato Julien Verrax Olivier Feron Pierre Sonveaux
author_facet	Christophe J De Saedeleer Tamara Copetti Paolo E Porporato Julien Verrax Olivier Feron Pierre Sonveaux
author_sort	Christophe J De Saedeleer
title	Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.
title_short	Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.
title_full	Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.
title_fullStr	Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.
title_full_unstemmed	Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.
title_sort	lactate activates hif-1 in oxidative but not in warburg-phenotype human tumor cells.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/9863463c24784addba273d7388d4e2f9
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Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells.

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