Journal
CELL DEATH & DISEASE
Volume 11, Issue 2, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-020-2224-7
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Funding
- Czech Science Foundation [1707635S, 18-02550S, 17-01192J, 17-20904S, 20-18513S, 19-20553S]
- Czech Health Science Foundation [17-30138A]
- BIOCEV European Regional Development Fund [CZ.1.05/1.100/02.0109]
- Institute of Biotechnology [RVO: 86652036]
- Grant Agency of Charles University [GA UK 1560218]
- CzechBioImaging large RI projects (MEYS CR) [LM2015062, CZ.02.1.01/0.0/0.0/16_013/0001775]
- FCT [SFRH/BD/103399/2014]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/103399/2014] Funding Source: FCT
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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.
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