Question

inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation

Answer 1

Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation

Abstract

Glucose fermentation through glycolysis even in the presence of oxygen (Warburg effect) is a common feature of cancer cells increasingly considered as an enticing target in clinical development. This study aimed to analyze the link between metabolism, energy stores and proliferation rates in cancer cells. We found that cell proliferation, evaluated by DNA synthesis quantification, is correlated to glycolytic efficiency in six cancer cell lines as well as in isogenic cancer cell lines. To further investigate the link between glycolysis and proliferation, a pharmacological inhibitior of the pentose phosphate pathway (PPP) was used. We demonstrated that reduction of PPP activity decreases cancer cells proliferation, with a profound effect in Warburg-phenotype cancer cells. The crucial role of the PPP in sustaining cancer cells proliferation was confirmed using siRNAs against glucose-6-phosphate dehydrogenase, the first and rate-limiting enzyme of the PPP. In addition, we found that dichloroacetate (DCA), a new clinically tested compound, induced a switch of glycolytic cancer cells to a more oxidative phenotype and decreased proliferation. By demonstrating that DCA decreased the activity of the PPP, we provide a new mechanism by which DCA controls cancer cells proliferation.

Keywords: bioenergetics, glycolysis, dichloroacetate, pentose phosphate pathway, proliferation

INTRODUCTION

These last few years, metabolism has generated tremendous interest in the field of cancer research. Many studies focused on the various metabolic profiles of different tumors [1–3] because metabolic plasticity is involved in cancer progression, drug resistance and metastasis [4–6]. In normal cells, glycolysis is coupled to oxidative phosphorylation (OXPHOS) to optimally synthesize intracellular ATP from glucose [7]. However, many cancer cells undergo a fundamental metabolic transformation, the “glycolytic switch”, by which glycolysis is uncoupled from respiration and rewired to lactic fermentation, thus becoming the primary source of cell ATP production. Switching to a glycolytic metabolism primarily occurs under hypoxia as a rescue mechanism for energy production. However, some cancer cells further adopt a particular glycolytic phenotype, first described by Warburg [8] and coined ‘aerobic glycolysis’ [9]. The biological rationale behind the Warburg phenotype remains controversial, but it has been recently proposed that proliferating cancer cells enhance glycolysis because it benefits both bioenergetics and biosynthesis [4, 10]. Indeed, a glycolytic metabolism potentially allows fast ATP production and provides carbon intermediates that can be directed to branched biosynthetic pathways, enabling a faster expansion of the cellular biomass. Convincingly, mutations occurring in signaling pathways regulating both cellular biosynthesis and aerobic glycolysis, such as the PI3K/Akt/mTOR pathway, are the most prevalent class of mutations in human tumors [11]. However, experimental evidence linking aerobic glycolysis to cancer cell proliferation is lacking, and the selective advantage provided by this phenotype is not entirely clear. The aim of the present study was to elucidate the coupling between metabolism, energy supply and cell proliferation in various human and murine cancer cells. Metabolic switches were induced to provide evidence that bioenergetics, and more particularly glycolysis, directly drives cancer cell proliferation. In this line, we found a new therapeutic mechanism of dichloroacetate (DCA), an activator of the mitochondrial oxidation of glucose currently investigated in clinical studies [12]. DCA inhibited the pentose phosphate pathway (PPP), a pivotal biosynthetic pathway branched to glycolysis. We report that the PPP bridges the gap between a glycolytic metabolism and cancer cell proliferation.