Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Activation of aerobic glycolysis in cancer cells is well known as the Warburg effect, although its relation to cell-cycle progression remains unknown. In this study, human colon cancer cells were labeled with a cell-cycle phase-dependent fluorescent marker Fucci to distinguish cells in G(1)-phase and those in S + G(2)/M phases. Fucci-labeled cells served as splenic xenograft transplants in super-immunodeficient NOG mice and exhibited multiple metastases in the livers, frozen sections of which were analyzed by semiquantitative microscopic imaging mass spectrometry. Results showed that cells in G(1)-phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G(2)-Mphases, suggesting accelerated glycolysis in G(1)-phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G2-M, and G(1) phases suggested that efflux of lactate was elevated significantly in G(1)-phase. By contrast, ATP production in G(2)-M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G(1) and G(2)-Mphases. Isogenic cells carrying a p53-null mutation appeared more active in glycolysis throughout the cell cycle than wild-type cells. Thus, as the cell cycle progressed from G(2)-M to G(1) phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased. (C) 2013 AACR.