Metabolic supervision by PPIP5K, an inositol pyrophosphate kinase/phosphatase, controls proliferation of the HCT116 tumor cell line

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  • Chunfang Gu
    Signal Transduction Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709;
  • Juan Liu
    Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710;
  • Xiaojing Liu
    Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710;
  • Haibo Zhang
    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892
  • Ji Luo
    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892
  • Huanchen Wang
    Signal Transduction Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709;
  • Jason W. Locasale
    Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710;
  • Stephen B. Shears
    Signal Transduction Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709;

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<jats:title>Significance</jats:title> <jats:p>Central carbon metabolism has the overlapping functions of converting substrate into biomass and the extraction and storage of chemical energy. These metabolic pathways are rewired by cancer cells to selectively support increased biomass demands. This reprogramming is a potential therapeutic target if a molecular-level understanding of the relevant control processes can be attained. Through genomic editing of an HCT116 colonic tumor cell line, we uncover metabolic supervision by a single pair of cell-signaling enzymes, the PPIP5Ks. Our global measurements of steady-state metabolite levels, plus isotope tracing analysis, show in detail how HCT116 cells recruit PPIP5Ks to select specific metabolic pathways to provide adequate precursor supply for biomass production. Crucially, in the absence of PPIP5K activity, HCT116 tumorigenesis is reduced.</jats:p>

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