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

PLoS One. 2012;7(10):e46571. doi: 10.1371/journal.pone.0046571. Epub 2012 Oct 17.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basigin / metabolism
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Proliferation / drug effects
  • Glycolysis / drug effects*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Lactic Acid / pharmacology*
  • Male
  • Mice
  • Mice, Nude
  • Monocarboxylic Acid Transporters / antagonists & inhibitors
  • Monocarboxylic Acid Transporters / metabolism
  • Neoplasms / blood supply
  • Neoplasms / pathology
  • Neovascularization, Pathologic / metabolism
  • Oxidation-Reduction / drug effects
  • Phenotype
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors
  • Procollagen-Proline Dioxygenase / metabolism
  • Protein Stability / drug effects
  • Symporters / antagonists & inhibitors
  • Symporters / metabolism

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Monocarboxylic Acid Transporters
  • Symporters
  • monocarboxylate transport protein 1
  • Basigin
  • Lactic Acid
  • EGLN1 protein, human
  • Procollagen-Proline Dioxygenase
  • Hypoxia-Inducible Factor-Proline Dioxygenases

Grant support

This work was supported by grants from the European Research Council (FP7/2007–2013 European Research Council Independent Researcher Starting Grant No. 243188 TUMETABO to P. Sonveaux), the Fonds National de la Recherche Scientifique (F.R.S.-FNRS), the Fonds de la Recherche Scientifique Médicale (FRSM), an Action de Recherche Concertée from the Communauté Française de Belgique (ARC 09/14-020 to O. Feron. and P. Sonveaux), the NEOANGIO research program from the Région Wallonne de Belgique (to O. Feron), the Fondation Belge contre le Cancer (200–2008 to O. Feron and P. Sonveaux), the Fonds Spéciaux de la Recherche (FSR) of the Université catholique de Louvain (UCL), and the J. Maisin and St. Luc Foundations (to O. Feron). O. Feron is an Honorary Research Director, P. Sonveaux is a Research Associate, and J. Verrax is a Postdoctoral Researcher of the F.R.S.-FNRS. C.J. De Saedeleer is a Télévie Research Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.