Lactate Activates HIF-1 in Oxidative but Not in Warburg-Phenotype Human Tumor Cells

Abstract

Cancer can be envisioned as a metabolic disease driven by pressure selection and intercellular cooperativeness. Together with anaerobic glycolysis, the Warburg effect, formally corresponding to uncoupling glycolysis from oxidative phosphorylation, directly participates in cancer aggressiveness, supporting both tumor progression and dissemination. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key contributor to glycolysis. It stimulates the expression of glycolytic transporters and enzymes supporting high rate of glycolysis. In this study, we addressed the reverse possibility of a metabolic control of HIF-1 in tumor cells. We report that lactate, the end-product of glycolysis, inhibits prolylhydroxylase 2 activity and activates HIF-1 in normoxic oxidative tumor cells but not in Warburg-phenotype tumor cells which also expressed lower basal levels of HIF-1α. These data were confirmed using genotypically matched oxidative and mitochondria-depleted glycolytic tumor cells as well as several different wild-type human tumor cell lines of either metabolic phenotype. Lactate activates HIF-1 and triggers tumor angiogenesis and tumor growth in vivo, an activity that we found to be under the specific upstream control of the lactate transporter monocarboxylate transporter 1 (MCT1) expressed in tumor cells. Because MCT1 also gates lactate-fueled tumor cell respiration and mediates pro-angiogenic lactate signaling in endothelial cells, MCT1 inhibition is confirmed as an attractive anticancer strategy in which a single drug may target multiple tumor-promoting pathways.

Regulation of the Expression and Activity of Glucose and Lactic Acid Metabolism-Related Genes by Protein Kinase C in Skeletal Muscle Cells

“…23) Recently, it was reported that lactic acid activated HIF-1 and triggers tumor angiogenesis and tumor growth. 24) Our results showed that PKC activation modulated glycolysis and lactic acid levels in RD cells. Collectively, we suggest that PKC inhibitor may lead to reduction in the chance of the rhabdomyosarcoma by inhibition of glycolysis and production of lactic acid.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…Whether lac tate is an in di rect in di ca tor of tu mor acid ity or ex erts it self a pro metasta tic ac tiv ity re mains to be fully elu ci dated; yet, tu mor lac tate map ping re vealed a lack of cor re la tion with pHe map ping [177], sug gest ing that pHe alone fails to ex plain why high lev els of lac tate are re lated to poor out come. As lac tate it self di rectly pro motes HIF sig nal ing [178,179], an gio gen e sis and tu mor pro gres sion [180,181], fu ture stud ies should be aimed to in ves ti gate the di rect role of lac tate in tu mor metas ta sis.…”

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

“…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).…”

“…In oxidative TCs and in endothelial cells, it shares with the metabolic lactate pathway the dependency on MCT1 and the need to oxidize lactate into pyruvate, but requires only a low rate of lactate uptake. [6][7][8] While TCs increase their production of vascular endothelial growth factor in response to lactate, 8,9 endothelial cells are triggered to upregulate the expression of vascular endothelial growth factor receptor 2, basic fibroblast growth factor, and interleukin-8, [6][7][8] thus providing several paracrine and autocrine pathways through which lactate induces angiogenesis. Additional activities of lactate in tumors have been reviewed recently.…”

“…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.…”