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  • Author
    Shivani Thaker
  • Co-author

    Milica Momcilovic, Ernst Schmid, Zhiyuan Mao, Daniel Braas, David Shackelford, & Heather R. Christofk

  • Title

    Ketohexokinase is important for lung tumor growth

  • Abstract

    Cancer cells and viruses reprogram cell metabolism towards increased nutrient uptake and anabolism. Unlike cancer cells, viruses undergo intense selection for efficiency, only upregulating metabolic nodes critical for their rapid replication. Viruses are therefore powerful tools to identify essential metabolic pathways in cancer cells. One of the most highly upregulated metabolic genes during adenovirus infection is ketohexokinase (KHK), which phosphorylates fructose to fructose 1-phosphate and is elevated across many patient cancers, including lung cancer. Here we show that KHK is important for lung cancer growth in vivo. Lung tumor xenograft growth is impaired by KHK knockout and rescued by expression of splice variant KHK-A, but not KHK-C. We further provide evidence that the polyol pathway, which converts intracellular glucose to fructose, supports cancer growth: we show that polyol pathway activity is increased in lung tumor xenografts relative to healthy lung and that KHK promotes nucleotide biosynthesis and cancer cell proliferation in the absence of exogenous fructose in vitro. Notably, essential fructosuria, a genetic condition in which individuals lack KHK activity, is asymptomatic. We hypothesize that targeting KHK, which is important for tumor growth but dispensable in healthy tissue, may effectively blunt tumor growth with limited systemic toxicities.

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