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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Cycle Checkpoints* / drug effects
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Cell Proliferation* / drug effects
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Checkpoint Kinase 1 / antagonists & inhibitors
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Checkpoint Kinase 1 / genetics
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Checkpoint Kinase 1 / metabolism
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Dihydroorotate Dehydrogenase
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Female
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Gene Expression Regulation, Neoplastic
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Genes, erbB-2
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HCT116 Cells
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Humans
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Leflunomide / pharmacology
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MCF-7 Cells
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, SCID
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Mice, Transgenic
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Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
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Oxidoreductases Acting on CH-CH Group Donors / genetics
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Oxidoreductases Acting on CH-CH Group Donors / metabolism
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Phenylurea Compounds / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Pyrazines / pharmacology
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Pyrimidines / biosynthesis*
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Ribosomes / genetics
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Ribosomes / metabolism*
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Signal Transduction
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Tumor Suppressor Protein p53 / deficiency*
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Tumor Suppressor Protein p53 / genetics
Substances
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Dihydroorotate Dehydrogenase
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LY2603618
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Pyrazines
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Pyrimidines
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TP53 protein, human
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Trp53 protein, mouse
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Tumor Suppressor Protein p53
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Oxidoreductases Acting on CH-CH Group Donors
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Leflunomide