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: | , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2012
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/9863463c24784addba273d7388d4e2f9 |
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| Sumario: | 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. |
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