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.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Hubackova S,Davidova E,Boukalova S,Kovarova J,Bajzikova M,Coelho A,Terp MG,Ditzel HJ,Rohlena J,Neuzil Jdoi
10.1038/s41419-020-2224-7subject
Has Abstractpub_date
2020-02-07 00:00:00pages
110issue
2issn
2041-4889pii
10.1038/s41419-020-2224-7journal_volume
11pub_type
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