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.

• MeSH
• checkpoint kinasa 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• fenylmočovinové sloučeniny farmakologie   MeSH
• geny erbB-2 MeSH
• HCT116 buňky MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kontrolní body buněčného cyklu * účinky léků   MeSH
• leflunomid farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myši inbrední BALB C MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši transgenní MeSH
• nádorový supresorový protein p53 nedostatek   genetika   MeSH
• nádory prsu farmakoterapie   genetika   metabolismus   patologie   MeSH
• oxidoreduktasy působící na CH-CH vazby antagonisté a inhibitory   genetika   metabolismus   MeSH
• proliferace buněk * účinky léků   MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   MeSH
• pyraziny farmakologie   MeSH
• pyrimidiny biosyntéza   MeSH
• regulace genové exprese u nádorů MeSH
• ribozomy genetika   metabolismus   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH