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.
Highlights
Cancer is a disease striving to match tumor cell ATP production and demand and to fulfill the biosynthetic needs for proliferation in a microenvironment heterogeneously providing oxygen and nutrients [1,2]
We first found that WiDr tumor cells (TCs) express significantly less basal levels of HIF-1a protein compared to SiHa TCs (Figure 1B)
Maintenance of a high rate of glycolysis is under the positive control of hypoxia-inducible factor-1 (HIF-1), a transcription factor associated with cancer aggressiveness and poor prognosis [43,44]
Summary
Cancer is a disease striving to match tumor cell ATP production and demand and to fulfill the biosynthetic needs for proliferation in a microenvironment heterogeneously providing oxygen and nutrients [1,2]. Full glucose oxidation to water and CO2 is an efficient mode of energy production generating up to 38 molecules of ATP per molecule of glucose It requires a functional coupling between glycolysis and oxidative phosphorylation (OXPHOS), and oxygen as the final electron acceptor of the respiratory chain. Glycolysis offers the necessary plasticity needed to fuel the biosynthetic pathways supporting cell proliferation [2]. To fulfill their proliferative agenda, tumor cells (TCs) evolve constitutive glycolysis, a metabolic phenotype known as the Warburg effect [4]. Mutations in mitochondrial enzymes have been identified in several cancer cell lines [5,6,7], increasing pieces of evidence indicate that the Warburg effect can most often be reverted pharmacologically [8,9,10]
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