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.

中文翻译：

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靶向嘧啶合成和细胞检查点引起的复制和核糖体应激抑制了p53缺陷型肿瘤。

p53突变的肿瘤通常表现出对标准化学疗法的抵抗力增强和转移潜力增强。在这里，我们证明抑制二氢乳清酸脱氢酶（DHODH），是从头嘧啶合成途径的关键酶，通过诱导p53和检查点激酶1（Chk1）依赖性复制和核糖体应激而有效降低癌细胞的增殖。从机制上讲，复制和核糖体生物发生的阻滞导致p53激活，同时伴随着复制叉的积累，这些叉激活了共济失调的毛细血管扩张和Rad3相关的激酶/ Chk1途径，两者均导致细胞周期停滞。由于在没有功能性p53的情况下，细胞周期停滞完全取决于Chk1，DHODH / Chk1联合抑制p53功能异常的癌细胞会诱导异常的细胞周期再进入和错误的有丝分裂，导致大量细胞死亡。联合的DHODH / Chk1抑制可有效抑制p53突变的肿瘤及其转移，因此为p53突变的癌症提供了有希望的治疗策略。