PMID- 26528183
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20151103
LR  - 20240323
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 6
DP  - 2015
TI  - Lactate does not activate NF-kappaB in oxidative tumor cells.
PG  - 228
LID - 10.3389/fphar.2015.00228 [doi]
LID - 228
AB  - The lactate anion is currently emerging as an oncometabolite. Lactate, produced 
      and exported by glycolytic and glutaminolytic cells in tumors, can be recycled as 
      an oxidative fuel by oxidative tumors cells. Independently of hypoxia, it can 
      also activate transcription factor hypoxia-inducible factor-1 (HIF-1) in tumor 
      and endothelial cells, promoting angiogenesis. These protumoral activities of 
      lactate depend on lactate uptake, a process primarily facilitated by the inward, 
      passive lactate-proton symporter monocarboxylate transporter 1 (MCT1); the 
      conversion of lactate and NAD(+) to pyruvate, NADH and H(+) by lactate 
      dehydrogenase-1 (LDH-1); and a competition between pyruvate and alpha-ketoglutarate 
      that inhibits prolylhydroxylases (PHDs). Endothelial cells do not primarily use 
      lactate as an oxidative fuel but, rather, as a signaling agent. In addition to 
      HIF-1, lactate can indeed activate transcription factor nuclear factor-kappaB (NF-kappaB) 
      in these cells, through a mechanism not only depending on PHD inhibition but also 
      on NADH alimenting NAD(P)H oxidases to generate reactive oxygen species (ROS). 
      While NF-kappaB activity in endothelial cells promotes angiogenesis, NF-kappaB activation 
      in tumor cells is known to stimulate tumor progression by conferring resistance 
      to apoptosis, stemness, pro-angiogenic and metastatic capabilities. In this 
      study, we therefore tested whether exogenous lactate could activate NF-kappaB in 
      oxidative tumor cells equipped for lactate signaling. We report that, precisely 
      because they are oxidative, HeLa and SiHa human tumor cells do not activate NF-kappaB 
      in response to lactate. Indeed, while lactate-derived pyruvate is well-known to 
      inhibit PHDs in these cells, we found that NADH aliments oxidative 
      phosphorylation (OXPHOS) in mitochondria rather than NAD(P)H oxidases in the 
      cytosol. These data were confirmed using oxidative human Cal27 and MCF7 tumor 
      cells. This new information positions the malate-aspartate shuttle as a key 
      player in the oxidative metabolism of lactate: similar to glycolysis that 
      aliments OXPHOS with pyruvate produced by pyruvate kinase and NADH produced by 
      glyceraldehyde-3-phosphate dehydrogenase (GAPDH), oxidative lactate metabolism 
      aliments OXPHOS in oxidative tumor cells with pyruvate and NADH produced by LDH1.
FAU - Van Hee, Vincent F
AU  - Van Hee VF
AD  - Pole of Pharmacology, Institut de Recherche Experimentale et Clinique, Universite 
      Catholique de Louvain (UCL) Medical School Brussels, Belgium.
FAU - Perez-Escuredo, Jhudit
AU  - Perez-Escuredo J
AD  - Pole of Pharmacology, Institut de Recherche Experimentale et Clinique, Universite 
      Catholique de Louvain (UCL) Medical School Brussels, Belgium.
FAU - Cacace, Andrea
AU  - Cacace A
AD  - Pole of Pharmacology, Institut de Recherche Experimentale et Clinique, Universite 
      Catholique de Louvain (UCL) Medical School Brussels, Belgium.
FAU - Copetti, Tamara
AU  - Copetti T
AD  - Pole of Pharmacology, Institut de Recherche Experimentale et Clinique, Universite 
      Catholique de Louvain (UCL) Medical School Brussels, Belgium.
FAU - Sonveaux, Pierre
AU  - Sonveaux P
AD  - Pole of Pharmacology, Institut de Recherche Experimentale et Clinique, Universite 
      Catholique de Louvain (UCL) Medical School Brussels, Belgium.
LA  - eng
GR  - 243188/ERC_/European Research Council/International
PT  - Journal Article
DEP - 20151013
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC4602127
OTO - NOTNLM
OT  - NAD(P)H oxidases (Nox)
OT  - NADH
OT  - cancer metabolism
OT  - lactate signaling
OT  - malate-aspartate shuttle
OT  - mitochondria
OT  - nuclear factor-kappaB
OT  - oxidative phosphorylation (OXPHOS)
EDAT- 2015/11/04 06:00
MHDA- 2015/11/04 06:01
PMCR- 2015/10/13
CRDT- 2015/11/04 06:00
PHST- 2015/08/08 00:00 [received]
PHST- 2015/09/25 00:00 [accepted]
PHST- 2015/11/04 06:00 [entrez]
PHST- 2015/11/04 06:00 [pubmed]
PHST- 2015/11/04 06:01 [medline]
PHST- 2015/10/13 00:00 [pmc-release]
AID - 10.3389/fphar.2015.00228 [doi]
PST - epublish
SO  - Front Pharmacol. 2015 Oct 13;6:228. doi: 10.3389/fphar.2015.00228. eCollection 
      2015.