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.
Highlights
These last few years, metabolism has generated tremendous interest in the field of cancer research
We found that cell proliferation evaluated by DNA synthesis was significantly correlated to glycolytic efficiency (Figure 1A), where increased glycolysis was associated with an increased proliferation capacity, and inversely
By performing DNA synthesis quantification, we found that enhanced aerobic glycolysis promotes cell proliferation, as the glycolytic switch in SiHa ρ0 cells was associated with a ~45% increase in cell proliferation (Figure 1F)
Summary
These last few years, metabolism has generated tremendous interest in the field of cancer research. 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]. 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 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]. We report that the PPP bridges the gap between a glycolytic metabolism and cancer cell proliferation
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