Abstract
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 G1-phase and those in S + G2/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 G1-phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G2-M phases, suggesting accelerated glycolysis in G1-phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G2-M, and G1 phases suggested that efflux of lactate was elevated significantly in G1-phase. By contrast, ATP production in G2-M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G1 and G2-M phases. 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 G2-M to G1 phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased. These results shed light on distinct features of the phase-specific phenotypes of metabolic systems in cancer cells.
Highlights
One of the most significant features of cancer cells is activation of glycolysis even under aerobic conditions
To study how energy metabolism is coordinated with cellcycle progression in cancer cells, we used human colon cancer HCT116 cells and their stable transfectants, FucciHCT116 cells, which were generated by introduction of the Fucci system into the parental cells
The results indicated that the cells collected at 3 hours were almost in S-phase (75%); those at 7 hours were in G2–M phase (85%); and those at 12 hours were in G1 phase (88%; Fig. 2B)
Summary
One of the most significant features of cancer cells is activation of glycolysis even under aerobic conditions. The feature, which has been termed Warburg Effect [1], is observed in cancer cells and in most of proliferating cells [2]. An increase in lactate production was found in G1 phase in HeLa cells [3]. Inhibition of glycolysis halted cell-cycle progression in G1 phase in HeLa cells [4]. Enhanced production of lactate with upregulation of gly-. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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