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Cell Metab. 2018 Nov 9. pii: S1550-4131(18)30646-6. doi: 10.1016/j.cmet.2018.10.014. [Epub ahead of print]

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

Author information

1
Institute of Biotechnology, Czech Academy of Sciences, 252 50, Vestec, Prague-West, Czech Republic; Faculty of Science, Charles University, 128 44 Prague, Czech Republic.
2
Institute of Biotechnology, Czech Academy of Sciences, 252 50, Vestec, Prague-West, Czech Republic. Electronic address: jaromira.kovarova@ibt.cas.cz.
3
Institute of Biotechnology, Czech Academy of Sciences, 252 50, Vestec, Prague-West, Czech Republic; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal.
4
Institute of Biotechnology, Czech Academy of Sciences, 252 50, Vestec, Prague-West, Czech Republic.
5
College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea.
6
School of Medical Science, Griffith University, Southport, QLD 4222, Australia.
7
Department of Developmental and Stem Cell Biology, Institut Pasteur, 75015 Paris, France; CNRS UMR 3738, Team Stability of Nuclear and Mitochondrial DNA, 75015 Paris, France.
8
Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
9
Faculty of Science, Charles University, 128 44 Prague, Czech Republic.
10
Institute of Molecular Genetics, Czech Academy of Sciences, 142 20 Prague, Czech Republic.
11
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal.
12
Institute for Glycomics, Griffith University, Southport, 4222 QLD, Australia.
13
Eunice Kennedy Shriver Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
14
Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, 6525 Nijmegen, the Netherlands.
15
Institute of Physiology, Czech Academy of Sciences, 142 20 Prague, Czech Republic.
16
Third Faculty Hospital, Charles University, Prague, Czech Republic.
17
Malaghan Institute of Medical Research, Wellington 6242, New Zealand.
18
College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Korea. Electronic address: psh@snu.ac.kr.
19
School of Medical Science, Griffith University, Southport, QLD 4222, Australia. Electronic address: l.dong@griffith.edu.au.
20
Institute of Biotechnology, Czech Academy of Sciences, 252 50, Vestec, Prague-West, Czech Republic. Electronic address: rohlenaj@ibt.cas.cz.
21
Institute of Biotechnology, Czech Academy of Sciences, 252 50, Vestec, Prague-West, Czech Republic; School of Medical Science, Griffith University, Southport, QLD 4222, Australia. Electronic address: j.neuzil@griffith.edu.au.

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.

KEYWORDS:

OXPHOS; cancer; coenzyme Q; dihydroorotate dehydrogenase; mitochondria; pyrimidine biosynthesis; respiration

PMID:
30449682
DOI:
10.1016/j.cmet.2018.10.014

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