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Title: Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells
Authors: Bajzikova, Martina 
Kovarova, Jaromira 
Coelho, Ana R. 
Boukalova, Stepana 
Oh, Sehyun 
Rohlenova, Katerina 
Svec, David 
Hubackova, Sona 
Endaya, Berwini 
Judasova, Kristyna 
Bezawork-Geleta, Ayenachew 
Kluckova, Katarina 
Chatre, Laurent 
Zobalova, Renata 
Novakova, Anna 
Vanova, Katerina 
Ezrova, Zuzana 
Maghzal, Ghassan J 
Magalhaes Novais, Silvia 
Olsinova, Marie 
Krobova, Linda 
An, Yong Jin 
Davidova, Eliska 
Nahacka, Zuzana 
Sobol, Margarita 
Cunha-Oliveira, Teresa 
Sandoval-Acuña, Cristian 
Strnad, Hynek 
Zhang, Tongchuan 
Huynh, Thanh 
Serafim, Teresa L. 
Hozak, Pavel 
Sardão, Vilma A. 
Koopman, Werner J H 
Ricchetti, Miria 
Oliveira, Paulo J 
Kolar, Frantisek 
Kubista, Mikael 
Truksa, Jaroslav 
Dvorakova-Hortova, Katerina 
Pacak, Karel 
Gurlich, Robert 
Stocker, Roland 
Zhou, Yaoqi 
Berridge, Michael V 
Park, Sunghyouk 
Dong, Lanfeng 
Rohlena, Jakub 
Neuzil, Jiri 
Issue Date: 5-Feb-2019
Serial title, monograph or event: Cell Metabolism
Volume: 29
Issue: 2
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.
ISSN: 1932-7420
DOI: 10.1016/j.cmet.2018.10.014
Rights: embargoedAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

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