Journal article

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

Martina Bajzikova, Jaromira Kovarova, Ana R Coelho, Stepana Boukalova, Sehyun Oh, Katerina Rohlenova, David Svec, Sona Hubackova, Berwini Endaya, Kristyna Judasova, Ayenachew Bezawork-Geleta, Katarina Kluckova, Laurent Chatre, Renata Zobalova, Anna Novakova, Katerina Vanova, Zuzana Ezrova, Ghassan J Maghzal, Silvia Magalhaes Novais, Marie Olsinova Show all

Cell Metabolism | CELL PRESS | Published : 2019

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 a..

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Grants

Awarded by Czech Science Foundation


Awarded by Czech Health Research Council


Awarded by Czech Academy of Sciences


Awarded by Ministry of Education, Youth and Sports of the Czech Republic


Awarded by ERDF


Awarded by National Health and Medical Research Council


Awarded by FCT - Foundation for Science and Technology


Awarded by National Health & Medical Research Council Senior Principal Research Fellowship


Awarded by Technology Agency of the Czech Republic


Awarded by framework of international cooperation program


Awarded by National Research Foundation of Korea (NRF) grant - Korea government (MSIT)


Awarded by DARRI


Awarded by FCT PhD scholarship


Awarded by Grant Agency of Charles University


Awarded by Czech-BioImaging large RI projects - MEYS CR


Awarded by MEYS CR


Awarded by EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT


Funding Acknowledgements

This work was supported in part by an Australian Research Council Discovery grant, Czech Science Foundation grants (15-02203S, 16-12719S, 17-07635S, and 17-0192J) and Czech Health Research Council grants (16-31604A and 17-30138A) to J.N., Czech Science Foundation grants (17-20904S and 1622823S) to J.R., a Czech Science Foundation grant (16-12816S) to J.T., Czech Science Foundation grant (18-24753Y) to D.S., Czech Science Foundation grant (18-11275S) to K.D.-H., Czech Science Foundation grant (18-02550S) to S.H., by the institutional support from Czech Academy of Sciences (RVO: 86652036), by the Ministry of Education, Youth and Sports of the Czech Republic within the LQ1604 National Sustainability Program II (Project BIOCEVFAR), and by the by the ERDF projects BIOCEV (CZ.1.05/1.100) and Mitenal (CZ.2.16/3.1.00/21531). Y.Z. was supported in part by the National Health and Medical Research Council (1059775 and 1083450). P.J.O. was funded in part by FEDER funds through the Operational Program Competitiveness Factors - COMPETE and national funds by FCT - Foundation for Science and Technology under projects PTDC/DTP-FTO/2433/2014, POCI-01-0145-FEDER-016659, POCI-01-0145-FEDER-007440, and POCI-01-0145-FEDER-016390: CANCEL STEM. R.S. acknowledges support from the National Health & Medical Research Council Senior Principal Research Fellowship 1111632, M.V.B. was supported by the Health Research Council of New Zealand, the Cancer Society of New Zealand and the Malaghan Institute, K.P. was supported by the Intramural Research Program of the NIH, NICHD, and M.S. and P.H. were supported by the Technology Agency of the Czech Republic (TE01020118). This work was also supported by the framework of international cooperation program (NRF-2016K2A9A1A06921853) and from a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2018R1A3B1052328). L.C. and M.R. were supported by DARRI (PasteurInnov 14/152). A.R.C. was supported by the FCT PhD scholarship SFRH/BD/103399/2014. M.B., Z.E., S.M.N., and E.D. were supported by the Grant Agency of Charles University (GA UK 362015, GA UK 1100217, GA UK 1552218, and GA UK 1560218, respectively). We acknowledge the Imaging Methods Core Facility at the BIOCEV supported by the Czech-BioImaging large RI projects (LM2015062 and CZ.02.1.01/0.0/0.0/16_013/0001775 Czech-BioImaging), funded by MEYS CR. We acknowledge as well the Electron Microscopy Core Facility at the IMG supported by the MEYS CR (LM2015062 Czech-BioImaging). We thank N.S. Chandel for providing the pWPI-AOX-IRES-GFP vector, C. Suarna for technical assistance with CoQ analysis, and C. Deus, T. Martins, and R. Couto for technical assistance with Seahorse analyses, and to T. Mracek for fruitful discussions.