Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation
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Géraldine De Preter1, Marie-Aline Neveu1, Pierre Danhier1, Lucie Brisson2, Valéry L. Payen2, Paolo E. Porporato2, Bénédicte F. Jordan1, Pierre Sonveaux2 and Bernard Gallez1
1 Louvain Drug Research Institute (LDRI), Biomedical Magnetic Resonance Research Group, Université Catholique de Louvain (UCL), Brussels, Belgium
2 Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology, Université Catholique de Louvain (UCL), Brussels, Belgium
Bernard Gallez, email:
Keywords: bioenergetics, glycolysis, dichloroacetate, pentose phosphate pathway, proliferation
Received: June 01, 2015 Accepted: September 26, 2015 Published: November 02, 2015
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.
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