Abstract
Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.
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28 August 2020
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Acknowledgements
This work was supported in part by the NIH grants (CA229307 and CA200573 to W.W.; CA183914 to L.W.; R01CA068490, P50CA101942 and R35CA210068 to W.G.K.), the National Basic Research Program of China (2015CB553602 to J.K.L.; 2015CB856302 to J.G.L.), the National Natural Science Foundation of China (91649106, 31570777, 31770917 and 31700684 to J.K.L.; 81802787 to Y.P.). Fundamental Research Funds for the Central Universities (08143008 and 08143101 to J.K.L.; zrzd2017013 to J.G.L.) and American Cancer Society (to H.I.). We thank Wangxiao He, Zhanwu Hou and Huadong Liu for their help with the peptide synthesis, thank Evan Chen for his kind help with metabolite labeling, and thank Brian J. North and Wei lab members for critical reading of the manuscript, and members of the Wei, Pandolfi, Kaelin and Liu laboratories for helpful discussions.
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J.L. and Y.P. designed and performed most of the experiments with assistance from L.S., L.W., H.I., J.G.L., J.P.G., J.Z., S.Z., X.W., J.G., X.D., S.F. and L.J., M.Y. and J.M.A. performed the LC-MS/MS metabolomic profiling and mass spectrometry analysis of IDH1 T157 phosphorylation. W.W., J.K.L., P.P.P., and W.G.K. supervised the study. J.L. and W.W. wrote the manuscript. All authors commented on the manuscript.
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W.W. is a co-founder and consultant of the ReKindle Therapeutics. All other authors declare no competing interests.
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Liu, J., Peng, Y., Shi, L. et al. Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle. Cell Res 31, 80–93 (2021). https://doi.org/10.1038/s41422-020-0372-z
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DOI: https://doi.org/10.1038/s41422-020-0372-z
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