367891 Metabolic Reprogramming of Glycolysis and Pentose Phosphate Pathway in Cancer Cells

Monday, November 17, 2014: 3:33 PM
206 (Hilton Atlanta)
Woo Suk Ahn, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA and Gregory Stephanopoulos, Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA

Cancer cells metabolize most glucose consumed to lactate production, a phenomenon known as the Warburg effect or aerobic glycolysis. Furthermore, cancer cells survive under nutrient-limited conditions to surpass normal cell growth. For example, oxygen-limited conditions significantly influences cancer cell metabolism by metabolic reprogramming; hypoxia aggravates the Warburg effect by elevating the conversion from glucose to lactate significantly at cancer cells because one oncogene, hypoxia-inducible factor (Hif) increases the expression of metabolic genes in glycolysis. Thus, the study of glycolytic metabolism under hypoxia provides valuable insight in understanding cancer metabolism and potentially discovering novel therapeutic targets. However, the simple measurement of the extracellular metabolites or gene expression levels can provide only limited information on cancer cell metabolism because glycolysis consists of reversible reactions and the pathway is also connected to the pentose phosphate pathway (PPP). Here, we quantified the metabolic fluxes of glycolysis and the PPP using 13C-metabolic flux analysis with human liver and breast cancer cell lines. Furthermore, we validated the observed metabolic behavior using shRNA knock-down cell lines, which contain reduced expression of metabolic genes in glycolysis and the PPP. In this course of study, surprisingly, we observed that hypoxic cancer cells show the metabolic rewiring of glycolysis and PPP. These results indicate the significant role of hypoxia in regulating between glycolytic and PPP metabolism as well as the activating of aerobic glycolysis in cancer cells. This study can be applied for drug development in cancer and metabolic disease as well as cell engineering.

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