Bajzikova, Martina and Kovarova, Jaromira and Coelho, Ana R. and Boukalova, Stepana and Oh, Sehyun and Rohlenova, Katerina and Svec, David and Hubackova, Sona and Endaya, Berwini and Judasova, Kristyna and Bezawork-Geleta, Ayenachew and Kluckova, Katarina and Chatre, Laurent and Zobalova, Renata and Novakova, Anna and Vanova, Katerina and Ezrova, Zuzana and Maghzal, Ghassan J and Magalhaes Novais, Silvia and Olsinova, Marie and Krobova, Linda and An, Yong Jin and Davidova, Eliska and Nahacka, Zuzana and Sobol, Margarita and Cunha-Oliveira, Teresa and Sandoval-Acuña, Cristian and Strnad, Hynek and Zhang, Tongchuan and Huynh, Thanh and Serafim, Teresa L. and Hozak, Pavel and Sardao, Vilma A. and Koopman, Werner J.H. and Ricchetti, Miria and Oliveira, Paulo J. and Kolar, Frantisek and Kubista, Mikael and Truksa, Jaroslav and Dvorakova-Hortova, Katerina and Pacak, Karel and Gurlich, Robert and Stocker, Roland and Zhou, Yaoqi and Berridge, Michael V. and Park, Sunghyouk and Dong, Lanfeng and Rohlena, Jakub and Neuzil, Jiri (2018) Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells. Cell Metabolism, ePub. pp. S1550-4131(18)30646-6. ISSN 15504131 (Not OA)
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 28 Nov 2018 22:09 |
| Last Modified: | 28 Nov 2018 22:15 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/776 |
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