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  • Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells

    Author(s)
    Bajzikova, Martina
    Kovarova, Jaromira
    Coelho, Ana R
    Boukalova, Stepana
    Oh, Sehyun
    Rohlenova, Katerina
    Svec, David
    Hubackova, Sona
    Endaya, Berwini
    Bezawork-Geleta, Ayenachew
    Novais, Silvia Magalhaes
    Zhang, Tongchuan
    Zhou, Yaoqi
    Dong, Lanfeng
    Neuzil, Jiri
    et al.
    Griffith University Author(s)
    Neuzil, Jiri
    Year published
    2019
    Metadata
    Show full item record
    Abstract
    Cancer cells without mitochondrial DNA (mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with ...
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    Cancer cells without mitochondrial DNA (mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox-cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents.
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    Journal Title
    Cell Metabolism
    Volume
    29
    Issue
    2
    DOI
    https://doi.org/10.1016/j.cmet.2018.10.014
    Subject
    Biochemistry and cell biology
    Medical biochemistry and metabolomics
    Oncology and carcinogenesis
    Publication URI
    http://hdl.handle.net/10072/384395
    Collection
    • Journal articles

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