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

Sona Hubackova*, Eliska Davidova, Stepana Boukalova, Jaromira Kovarova, Martina Bajzikova, Ana Coelho, Mikkel G. Terp, Henrik J. Ditzel, Jakub Rohlena, Jiri Neuzil

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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 p53-dysfunctional 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.

Original languageEnglish
Article number110
JournalCell Death and Disease
Volume11
Issue number2
Number of pages16
ISSN2041-4889
DOIs
Publication statusPublished - 1. Feb 2020

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