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Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells
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SYSNO ASEP 0504151 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells Author(s) Bajziková, Martina (BTO-N) RID
Kovářová, Jaromíra (BTO-N) RID
Coelho, Ana R. (BTO-N)
Boukalová, Štěpána (BTO-N)
Oh, S. (KR)
Rohlenová, Kateřina (BTO-N) ORCID, RID
Švec, David (BTO-N) RID
Hubáčková, Soňa (BTO-N)
Endaya, B. (AU)
Judasová, Kateřina (BTO-N)
Bezawork-Geleta, A. (AU)
Klučková, Katarína (BTO-N) RID
Chatre, L. (FR)
Zobalová, Renata (BTO-N) RID
Nováková, Anna (BTO-N)
Váňová, Kateřina (BTO-N)
Ezrová, Zuzana (BTO-N) ORCID
Maghzal, G. J. (AU)
Novais, Silvia Magalhaes (BTO-N)
Olsinova, M. (CZ)
Krobová, Linda (BTO-N)
An, Y. J. (KR)
Davidová, Eliška (BTO-N)
Nahácka, Zuzana (BTO-N)
Sobol, Margaryta (UMG-J) RID
Cunha-Oliveira, T. (PT)
Sandoval-Acuna, Cristian (BTO-N)
Strnad, Hynek (UMG-J) RID
Zhang, T. (AU)
Huynh, T. (US)
Serafim, T. L. (AU)
Hozák, Pavel (UMG-J) RID, ORCID
Sardao, V. A. (PT)
Koopman, W. J. H. (NL)
Ricchetti, M. (FR)
Oliveira, P. J. (PT)
Kolář, František (FGU-C) RID, ORCID, SAI
Kubista, Mikael (BTO-N) RID
Truksa, Jaroslav (BTO-N) RID, ORCID
Dvořáková-Hortová, Kateřina (BTO-N)
Pacak, K. (US)
Gürlich, R. (CZ)
Stocker, R. (AU)
Zhou, Y. (AU)
Berridge, M.V. (AU)
Park, S. (KR)
Dong, L. (AU)
Rohlena, Jakub (BTO-N) RID, ORCID
Neužil, Jiří (BTO-N) RIDNumber of authors 49 Source Title Cell Metabolism. - : Cell Press - ISSN 1550-4131
Roč. 29, č. 2 (2019), s. 399-416Number of pages 18 s. Language eng - English Country US - United States Keywords ELECTRON-TRANSPORT CHAIN ; PANCREATIC-CANCER ; MITOCHONDRIA Subject RIV EB - Genetics ; Molecular Biology OECD category Cell biology Subject RIV - cooperation Institute of Physiology - Physiology
Institute of Molecular Genetics - Genetics ; Molecular BiologyR&D Projects GA15-02203S GA ČR - Czech Science Foundation (CSF) GA16-12719S GA ČR - Czech Science Foundation (CSF) GA17-20904S GA ČR - Czech Science Foundation (CSF) GA16-22823S GA ČR - Czech Science Foundation (CSF) GA16-12816S GA ČR - Czech Science Foundation (CSF) GA18-11275S GA ČR - Czech Science Foundation (CSF) GA18-02550S GA ČR - Czech Science Foundation (CSF) NV16-31604A GA MZd - Ministry of Health (MZ) NV17-30138A GA MZd - Ministry of Health (MZ) LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2015062 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GJ18-24753Y GA ČR - Czech Science Foundation (CSF) EF16_013/0001775 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support BTO-N - RVO:86652036 ; FGU-C - RVO:67985823 ; UMG-J - RVO:68378050 UT WOS 000457708100017 EID SCOPUS 85060704969 DOI 10.1016/j.cmet.2018.10.014 Annotation 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. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2020 Electronic address https://www.sciencedirect.com/science/article/pii/S1550413118306466?via%3Dihub
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