Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/84850
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. | URI: | https://hdl.handle.net/10316/84850 | ISSN: | 1932-7420 | DOI: | 10.1016/j.cmet.2018.10.014 | Rights: | embargoedAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
34_Bajzikova2018_CellMetabolism.pdf | 5.19 MB | Adobe PDF | View/Open |
SCOPUSTM
Citations
178
checked on Aug 26, 2024
WEB OF SCIENCETM
Citations
5
174
checked on Aug 2, 2024
Page view(s)
271
checked on Aug 27, 2024
Download(s)
282
checked on Aug 27, 2024
Google ScholarTM
Check
Altmetric
Altmetric
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.