Abstract
Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) represents an attractive therapeutic strategy but may stimulate glucose consumption by oxidative cancer cells. We report here that inhibition of mitochondrial pyruvate carrier (MPC) activity fulfils the tasks of blocking lactate use while preventing glucose oxidative metabolism. Using in vitro 13C-glucose and in vivo hyperpolarized 13C-pyruvate, we identify 7ACC2 as a potent inhibitor of mitochondrial pyruvate transport which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation. Also, while in spheroids MCT1 inhibition leads to cytostatic effects, MPC activity inhibition induces cytotoxic effects together with glycolysis stimulation and uncompensated inhibition of mitochondrial respiration. Hypoxia reduction obtained with 7ACC2 is further shown to sensitize tumor xenografts to radiotherapy. This study positions MPC as a control point for lactate metabolism and expands on the anticancer potential of MPC inhibition.
Highlights
Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth
The scarcity of nutrients further reinforces the concept of metabolic symbiosis: limitations in glucose availability at some distance of blood vessels may be partly attenuated by the lesser consumption of glucose by the most oxygenated cancer cells that fuel their metabolism with lactate
The lesser affinity of SiHa for glucose as an oxidative fuel was neither involved since the use of FaDu and MCF-7 cells that exhibit a similar capacity of glucose and lactate to support O2 consumption rate (OCR) confirmed the differential sensitivity to either compound (Supplementary Fig. 1c)
Summary
Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) represents an attractive therapeutic strategy but may stimulate glucose consumption by oxidative cancer cells. We report here that inhibition of mitochondrial pyruvate carrier (MPC) activity fulfils the tasks of blocking lactate use while preventing glucose oxidative metabolism. Tumor lactate-based metabolic symbiosis describes the winwin interaction between lactate-generating and lactateconsuming cells in solid cancers[1,2] This concept is known for a while in muscle physiology[3,4]. In the latter study and another one using genetically engineered mouse models for lung cancer[17], the contribution of lactate to TCA cycle intermediates was further shown to exceed that of glucose; these studies validate that blood-borne (and tumor-derived) lactate may fuel oxidative cancer cells. To more concretely evaluate the clinical potential of targeting metabolic pathways, pharmacological strategies need to be confronted with the issue of drug distribution within distinct tumor compartments
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