PMID- 23082126
OWN - NLM
STAT- MEDLINE
DCOM- 20130409
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 10
DP  - 2012
TI  - Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor 
      cells.
PG  - e46571
LID - 10.1371/journal.pone.0046571 [doi]
LID - e46571
AB  - 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-1alpha. 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.
FAU - De Saedeleer, Christophe J
AU  - De Saedeleer CJ
AD  - Pole of Pharmacology, Institut de Recherches Experimentales et Cliniques (IREC), 
      Universite catholique de Louvain (UCL), Brussels, Belgium.
FAU - Copetti, Tamara
AU  - Copetti T
FAU - Porporato, Paolo E
AU  - Porporato PE
FAU - Verrax, Julien
AU  - Verrax J
FAU - Feron, Olivier
AU  - Feron O
FAU - Sonveaux, Pierre
AU  - Sonveaux P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121017
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Monocarboxylic Acid Transporters)
RN  - 0 (Symporters)
RN  - 0 (monocarboxylate transport protein 1)
RN  - 136894-56-9 (Basigin)
RN  - 33X04XA5AT (Lactic Acid)
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
MH  - Animals
MH  - Basigin/metabolism
MH  - Cell Line, Tumor
MH  - Cell Membrane/drug effects/metabolism
MH  - Cell Proliferation/drug effects
MH  - Glycolysis/*drug effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases
MH  - Lactic Acid/*pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Monocarboxylic Acid Transporters/antagonists & inhibitors/metabolism
MH  - Neoplasms/blood supply/pathology
MH  - Neovascularization, Pathologic/metabolism
MH  - Oxidation-Reduction/drug effects
MH  - Phenotype
MH  - Procollagen-Proline Dioxygenase/antagonists & inhibitors/metabolism
MH  - Protein Stability/drug effects
MH  - Symporters/antagonists & inhibitors/metabolism
PMC - PMC3474765
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/10/20 06:00
MHDA- 2013/04/10 06:00
PMCR- 2012/10/17
CRDT- 2012/10/20 06:00
PHST- 2012/05/16 00:00 [received]
PHST- 2012/08/31 00:00 [accepted]
PHST- 2012/10/20 06:00 [entrez]
PHST- 2012/10/20 06:00 [pubmed]
PHST- 2013/04/10 06:00 [medline]
PHST- 2012/10/17 00:00 [pmc-release]
AID - PONE-D-12-14269 [pii]
AID - 10.1371/journal.pone.0046571 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(10):e46571. doi: 10.1371/journal.pone.0046571. Epub 2012 Oct 17.