(6ge) Metabolic reprogramming of hypoxic cancer cells

Cancer cells survive under nutrient-limited conditions to surpass normal cell growth. For example, oxygen-limited conditions significantly influence cancer cell metabolism; hypoxia aggravates the Warburg effect by elevating the conversion from glucose to lactate significantly in cancer cells because one oncogene, hypoxia-inducible factor (Hif) increases the expression of metabolic genes in glycolysis. Consequently, it inhibits pyruvate dehydrogenase via activating pyruvate dehydrogenase kinase to decrease oxidative phosphorylation in the TCA cycle. These are key events in tumorigenesis and proliferating cells. Thus, the study of cancer metabolism under hypoxia provides valuable insights in understanding cancer progression and potentially discovering novel therapeutic targets. However, the simple measurement of extracellular metabolites or gene expression levels can provide only limited information on cancer metabolism because most in vivo metabolic fluxes consist of reversible reactions and metabolic pathways are also connected to each other. Here, we quantified the metabolic fluxes covering glycolysis, the pentose phosphate pathway and the TCA cycle using ¹³C-metabolic flux analysis with human cancer cell lines. Furthermore, we validated the observed metabolic behaviors using shRNA knock-down and over-expression cell lines for specific genes. In this course of study, we identified the significant role of hypoxia in regulating cancer cell growth through molecular regulation and metabolic reprogramming by the Hif oncogene.