Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors

0535103 - BTÚ 2021 RIV GB eng J - Journal Article
Hubáčková, Soňa - Davidová, Eliška - Boukalová, Štěpána - Kovářová, Jaromíra - Bajziková, Martina - Coelho, Ana R. - Terp, M. G. - Ditzel, H. J. - Rohlena, Jakub - Neužil, Jiří
Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress p53-deficient tumors.
Cell Death & Disease. Roč. 11, č. 2 (2020), č. článku 110. ISSN 2041-4889. E-ISSN 2041-4889
R&D Projects: GA ČR(CZ) GA17-07635S; GA ČR(CZ) GA18-02550S; GA ČR(CZ) GC17-01192J; GA ČR GA17-20904S; GA ČR(CZ) GA20-18513S; GA ČR GA19-20553S; GA MZd(CZ) NV17-30138A
Institutional support: RVO:86652036
Keywords : de-novo synthesis * dihydroorotate dehydrogenase * dna-replication * protein l11 * inhibition
OECD category: Cell biology
Impact factor: 8.469, year: 2020
Method of publishing: Open access
https://www.nature.com/articles/s41419-020-2224-7.pdf

p53-mutated tumors often exhibit increased resistance to standard chemotherapy and enhanced metastatic potential. Here we demonstrate that inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme of the de novo pyrimidine synthesis pathway, effectively decreases proliferation of cancer cells via induction of replication and ribosomal stress in a p53- and checkpoint kinase 1 (Chk1)-dependent manner. Mechanistically, a block in replication and ribosomal biogenesis result in p53 activation paralleled by accumulation of replication forks that activate the ataxia telangiectasia and Rad3-related kinase/Chk1 pathway, both of which lead to cell cycle arrest. Since in the absence of functional p53 the cell cycle arrest fully depends on Chk1, combined DHODH/Chk1 inhibition in p53dysfunctional cancer cells induces aberrant cell cycle re-entry and erroneous mitosis, resulting in massive cell death. Combined DHODH/Chk1 inhibition effectively suppresses p53-mutated tumors and their metastasis, and therefore presents a promising therapeutic strategy for p53-mutated cancers.
Permanent Link: http://hdl.handle.net/11104/0313253