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


: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.


Cell Death Dis


Cell death & disease


Hubackova S,Davidova E,Boukalova S,Kovarova J,Bajzikova M,Coelho A,Terp MG,Ditzel HJ,Rohlena J,Neuzil J




Has Abstract


2020-02-07 00:00:00












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    authors: Lei WW,Zhang KH,Pan XC,Wang DM,Hu Y,Yang YN,Song JG

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    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Fujita Y,Takashima R,Endo S,Takai T,Yamashita T

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    pub_type: 杂志文章,评审


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    pub_type: 杂志文章


    authors: Guttà C,Rahman A,Aura C,Dynoodt P,Charles EM,Hirschenhahn E,Joseph J,Wouters J,de Chaumont C,Rafferty M,Warren M,van den Oord JJ,Gallagher WM,Rehm M

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    journal_title:Cell death & disease

    pub_type: 已发布勘误


    authors: Roger E,Martel S,Bertrand-Chapel A,Depollier A,Chuvin N,Pommier RM,Yacoub K,Caligaris C,Cardot-Ruffino V,Chauvet V,Aires S,Mohkam K,Mabrut JY,Adham M,Fenouil T,Hervieu V,Broutier L,Castets M,Neuzillet C,Cassier PA,

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    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Lei R,Zhang K,Liu K,Shao X,Ding Z,Wang F,Hong Y,Zhu M,Li H,Li H

    更新日期:2016-06-30 00:00:00

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    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Kong Y,Hu L,Lu K,Wang Y,Xie Y,Gao L,Yang G,Xie B,He W,Chen G,Wu H,Wu X,Zhan F,Shi J

    更新日期:2019-08-19 00:00:00