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

0504151 - BTÚ 2020 RIV US eng J - Journal Article
Bajziková, Martina - Kovářová, Jaromíra - Coelho, Ana R. - Boukalová, Štěpána - Oh, S. - Rohlenová, Kateřina - Švec, David - Hubáčková, Soňa - Endaya, B. - Judasová, Kateřina - Bezawork-Geleta, A. - Klučková, Katarína - Chatre, L. - Zobalová, Renata - Nováková, Anna - Váňová, Kateřina - Ezrová, Zuzana - Maghzal, G. J. - Novais, Silvia Magalhaes - Olsinova, M. - Krobová, Linda - An, Y. J. - Davidová, Eliška - Nahácka, Zuzana - Sobol, Margaryta - Cunha-Oliveira, T. - Sandoval-Acuna, Cristian - Strnad, Hynek - Zhang, T. - Huynh, T. - Serafim, T. L. - Hozák, Pavel - Sardao, V. A. - Koopman, W. J. H. - Ricchetti, M. - Oliveira, P. J. - Kolář, František - Kubista, Mikael - Truksa, Jaroslav - Dvořáková-Hortová, Kateřina - Pacak, K. - Gürlich, R. - Stocker, R. - Zhou, Y. - Berridge, M.V. - Park, S. - Dong, L. - Rohlena, Jakub - Neužil, Jiří
Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells.
Cell Metabolism. Roč. 29, č. 2 (2019), s. 399-416. ISSN 1550-4131. E-ISSN 1932-7420
R&D Projects: GA ČR GA15-02203S; GA ČR GA16-12719S; GA ČR GA17-20904S; GA ČR GA16-22823S; GA ČR(CZ) GA16-12816S; GA ČR(CZ) GA18-11275S; GA ČR(CZ) GA18-02550S; GA MZd(CZ) NV16-31604A; GA MZd(CZ) NV17-30138A; GA MŠMT(CZ) LQ1604; GA MŠMT(CZ) LM2015062; GA ČR(CZ) GJ18-24753Y; GA MŠMT(CZ) EF16_013/0001775
Institutional support: RVO:86652036 ; RVO:67985823 ; RVO:68378050
Keywords : ELECTRON-TRANSPORT CHAIN * PANCREATIC-CANCER * MITOCHONDRIA
OECD category: Cell biology; Physiology (including cytology) (FGU-C); Cell biology (UMG-J)
Impact factor: 21.567, year: 2019
Method of publishing: Open access
https://www.sciencedirect.com/science/article/pii/S1550413118306466?via%3Dihub

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.
Permanent Link: http://hdl.handle.net/11104/0295861