Skip to Content
MilliporeSigma
  • Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells.

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

Cell metabolism (2018-11-20)
Martina Bajzikova, Jaromira Kovarova, Ana R Coelho, Stepana Boukalova, Sehyun Oh, Katerina Rohlenova, David Svec, Sona Hubackova, Berwini Endaya, Kristyna Judasova, Ayenachew Bezawork-Geleta, Katarina Kluckova, Laurent Chatre, Renata Zobalova, Anna Novakova, Katerina Vanova, Zuzana Ezrova, Ghassan J Maghzal, Silvia Magalhaes Novais, Marie Olsinova, Linda Krobova, Yong Jin An, Eliska Davidova, Zuzana Nahacka, Margarita Sobol, Teresa Cunha-Oliveira, Cristian Sandoval-Acuña, Hynek Strnad, Tongchuan Zhang, Thanh Huynh, Teresa L Serafim, Pavel Hozak, Vilma A Sardao, Werner J H Koopman, Miria Ricchetti, Paulo J Oliveira, Frantisek Kolar, Mikael Kubista, Jaroslav Truksa, Katerina Dvorakova-Hortova, Karel Pacak, Robert Gurlich, Roland Stocker, Yaoqi Zhou, Michael V Berridge, Sunghyouk Park, Lanfeng Dong, Jakub Rohlena, Jiri Neuzil
PMID30449682
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 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.