title: 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 inhibitor 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.
authors.affiliation: Louvain Drug Research Institute (LDRI), Biomedical Magnetic Resonance Research Group, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Géraldine
authors.initials: G
authors.lastname: De Preter
authors.affiliation: Louvain Drug Research Institute (LDRI), Biomedical Magnetic Resonance Research Group, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Marie-Aline
authors.initials: MA
authors.lastname: Neveu
authors.affiliation: Louvain Drug Research Institute (LDRI), Biomedical Magnetic Resonance Research Group, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Danhier
authors.affiliation: Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Lucie
authors.initials: L
authors.lastname: Brisson
authors.affiliation: Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Valéry L
authors.initials: VL
authors.lastname: Payen
authors.affiliation: Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Paolo E
authors.initials: PE
authors.lastname: Porporato
authors.affiliation: Louvain Drug Research Institute (LDRI), Biomedical Magnetic Resonance Research Group, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Jordan
authors.affiliation: Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.affiliation: Louvain Drug Research Institute (LDRI), Biomedical Magnetic Resonance Research Group, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology; D010427:Pentose Phosphate Pathway / Q000187:drug effects* / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid; D005954:Glucosephosphate Dehydrogenase; D005947:Glucose
keywords: bioenergetics; dichloroacetate; glycolysis; pentose phosphate pathway; proliferation