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

Abstract

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 α-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.

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

“…As CD147 beyond MCT1 associates with a number of partners (including MCT4) to form supercomplexes, 39 additional and perhaps more indirect influences cannot be excluded. Furthermore, additional controls would be involved under hypoxia, [40][41][42] explaining why hypoxia can fail to induce or can even repress MCT1 expression in vivo 3,43 whereas it stimulates MCT1 expression in vitro 44 (Figure 2a), and why we detected increased MCT1 expression at early time points (Figure 2a, 24 h) whereas others did not find MCT1 induction upon a longer exposure to hypoxia (48 h). 5 Modulating ROS can indeed impact the response of MCT1 to hypoxia (Supplementary Figure 4A).…”

“…SiHa cell death upon glucose removal was rescued with lactate ( Supplementary Figure 2A), a substrate known to efficiently replace glucose as an oxidative fuel for these cells. 3 Western blots further showed that lactate totally suppressed the induction of MCT1 and CD147 expression that was otherwise detected 48 h after glucose removal (Figure 3a). It was confirmed using the two SiHa clones (Supplementary Figure 2E) and HeLa cells (Supplementary Figure 2F).…”

“…It was experimentally induced by depriving cells of glucose in a medium containing no glutamine, pyruvate, lactate or serum, and an equal amount of viable TCs were systematically compared. As models, we used SiHa cells that were previously documented to rely on OXPHOS for energy production 3,8 and HeLa cells known for their ability to switch from a glucose to a glutamine-(i.e., OXPHOS-dependent) fueled metabolism. 18 In a first series of experiments, we observed a dose-dependent increase in MCT1 and CD147 protein expression in SiHa cells cultured during 48 h with decreasing glucose concentrations ( Figure 1a).…”

“…2 Lactate shuttles first account for a metabolic symbiosis in tumors wherein oxygenated TCs import lactate to fuel oxidative phosphorylation (OXPHOS) through the tricarboxylic acid (TCA) cycle. 3 The preferential use of lactate by these cells allows glucose to diffuse farther from blood vessels at a maximal theoretical rate of 1 glucose molecule spared for 2 molecules of lactate used. It primarily depends on the expression and activity of monocarboxylate transporter 1 (MCT1), a passive lactate-proton symporter facilitating lactic acid uptake by oxidative TCs (whereas MCT4 channels lactic acid out of glycolytic TCs).…”

“…10 Conversely, MCT1 inhibition has been well documented preclinically to exert antimetabolic and anti-angiogenic effects leading to hypoxic/ glycolytic TC death by virtue of glucose starvation. 3,[6][7][8] A first orally-available MCT1 inhibitor having demonstrated preclinical safety is currently entering into clinical trials. 1 Despite the fact that MCT1 has emerged as a new anticancer target, there is only limited general knowledge about the molecular mechanisms governing its expression and activity.…”