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.