Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced angiogenesis
Tamara
Copetti1,
Christophe
J.
De Saedeleer1,
Frédérique
Végran1,
Julien
Verrax1,
Kelly
M.
Kennedy2,
Eui Jung
Moon3,
Suveera
Dhup1,
Pierre
Danhier4,
Françoise
Frérart1,
Bernard
Gallez4,
Anthony
Ribeiro5,
Carine
Michiels6,
Mark
W.
Dewhirst2, 3,
Olivier
Feron1 and
Pierre
Sonveaux1*
-
1
Université catholique de Louvain (UCL), Institut de Recherche Expérimentale et Clinique (IREC), Belgium
-
2
Duke University Medical Center, Radiation Oncology, United States
-
3
Duke University Medical Center, Pathology, United States
-
4
Université catholique de Louvain (UCL), Louvain Drug Research Institute (LDRI), Belgium
-
5
Duke University Medical Center, Radiology and Biochemistry, United States
-
6
University of Namur, Biochemistry and Cellular Biology, Belgium
Background and aim. Glycolysis is the primary source of ATP in hypoxic tumor cells. Compared to oxidative phosphorylation, it is a rather inefficient process to produce ATP but hypoxic tumor cells accelerate the glycolytic flux in order to match ATP production and demand, which is associated with high glucose consumption and high lactate release. We previously showed that lactate is biologically active in tumors: it is recycled as an oxidative fuel for oxygenated tumor cells. We now tested whether lactate exchanges also influence endothelial cell (EC) metabolism.
Methods. Human umbilical vein ECs (HUVECs) and bovine aortic ECs (BAECs) were used as in vitro cell models, aortic rings for ex vivo sprouting angiogenesis, and intravital microscopy for in vivo assays. Lactate was used as a sodium salt at concentrations (1-10 mM) commonly found in human tumors. It was measured using 13C-NMR and enzymatic assays.
Results. We found that ECs express the lactate transporter monocarboxylate transporter 1 (MCT1), which we had previously identified as the major facilitator of lactate uptake by tumor cells. Although ECs took up lactate, they did not primarily use it as a metabolic fuel. Lactate rather acted as a hypoxia-mimetic that activated the transcription factor hypoxia-inducible factor-1 (HIF-1) under normoxic conditions and, downstream, basic fibroblast growth factor (bFGF) production and vascular endothelial growth factor (VEGF) receptor 2 expression. At the molecular level, we showed that lactate oxidation to pyruvate by lactate dehydrogenase 1 (LDH1) is crucial to engage a competition between pyruvate and 2-oxoglutarate, which eventually leads to inhibition of the canonical HIF-1α degradation pathway. Using pharmacological inhibitors and RNA interference, we further evidenced that MCT1 inhibition prevents lactate-induced HIF-1 activation, EC migration, tube formation and endothelial sprouting. Using intravital microscopy and tumor cells insensitive to the antimetabolic effects of MCT1 inhibition, we finally provided evidence that MCT1 inhibition blocks tumor angiogenesis in vivo.
Conclusions. Our study demonstrates that lactate triggers a pro-angiogenic conversion of ECs that can be blocked with MCT1 inhibitors. Because MCT1 is also a key regulator of lactate exchanges between tumor cells, targeting MCT1 could offer the unique opportunity to combine antimetabolic and anti-angiogenic effects within a same therapeutic agent.
Acknowledgements
This work was supported by ERC Starting Grant 243188 TUMETABO to Pierre Sonveaux.
Keywords:
Angiogenesis,
Cancer,
HIF-1,
endothelial cell,
VEGFR-2,
bFGF,
mct1
Conference:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013.
Presentation Type:
Abstract
Topic:
2. Membrane transporter in intracellular and extracellular pH-control
Citation:
Copetti
T,
De Saedeleer
CJ,
Végran
F,
Verrax
J,
Kennedy
KM,
Moon
E,
Dhup
S,
Danhier
P,
Frérart
F,
Gallez
B,
Ribeiro
A,
Michiels
C,
Dewhirst
MW,
Feron
O and
Sonveaux
P
(2014). Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced angiogenesis.
Front. Pharmacol.
Conference Abstract:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer.
doi: 10.3389/conf.fphar.2014.61.00015
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Received:
16 Dec 2013;
Published Online:
07 Feb 2014.
*
Correspondence:
Prof. Pierre Sonveaux, Université catholique de Louvain (UCL), Institut de Recherche Expérimentale et Clinique (IREC), Brussels, 1200, Belgium, pierre.sonveaux@uclouvain.be