1: J Clin Invest. 2008 Dec;118(12):3930-42. doi: 10.1172/JCI36843. Epub 2008 Nov 
20.

Comment in:
    J Clin Invest. 2008 Dec;118(12):3835-7.

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in
mice.

Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer 
CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O,
Dewhirst MW.

Unit of Pharmacology & Therapeutics, Université catholique de Louvain, Brussels, 
Belgium. pierre.sonveaux@uclouvain.be

Tumors contain oxygenated and hypoxic regions, so the tumor cell population is
heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy
production and release lactic acid, creating a lactate gradient that mirrors the 
oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been
thought to primarily use glucose for oxidative energy production. Although
lactate is generally considered a waste product, we now show that it is a
prominent substrate that fuels the oxidative metabolism of oxygenated tumor
cells. There is therefore a symbiosis in which glycolytic and oxidative tumor
cells mutually regulate their access to energy metabolites. We identified
monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by 
a human cervix squamous carcinoma cell line that preferentially utilized lactate 
for oxidative metabolism. Inhibiting MCT1 with alpha-cyano-4-hydroxycinnamate
(CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to
glycolysis. A similar switch from lactate-fueled respiration to glycolysis by
oxygenated tumor cells in both a mouse model of lung carcinoma and
xenotransplanted human colorectal adenocarcinoma cells was observed after
administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic
tumor cells died from glucose starvation, and rendered the remaining cells
sensitive to irradiation. As MCT1 was found to be expressed by an array of
primary human tumors, we suggest that MCT1 inhibition has clinical antitumor
potential.


PMID: 19033663 [PubMed - indexed for MEDLINE]

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