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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Replication and ribosomal stress induced by targeting pyrimidine synthesis and cellular checkpoints suppress

Sona Hubackova1, Eliska Davidova2,3, Stepana Boukalova2

  • 1Laboratory of Molecular Therapy, Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 252 50, Czech Republic. sona.hubackova@ibt.cas.cz.

Cell Death & Disease
|February 9, 2020
PubMed

Insights

Inhibiting dihydroorotate dehydrogenase (DHODH) and checkpoint kinase 1 (Chk1) in p53-mutated cancers induces cell death. This combined therapy effectively suppresses tumor growth and metastasis, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • p53-mutated tumors display resistance to chemotherapy and increased metastasis.
  • Dihydroorotate dehydrogenase (DHODH) is crucial for de novo pyrimidine synthesis.

Purpose of the Study:

  • To investigate the therapeutic potential of DHODH inhibition in p53-mutated cancers.
  • To elucidate the mechanisms underlying DHODH inhibition-induced cancer cell death.

Main Methods:

  • Inhibition of DHODH and/or checkpoint kinase 1 (Chk1) in cancer cell lines and p53-mutated tumor models.
  • Analysis of cell proliferation, cell cycle arrest, replication stress, and ribosomal biogenesis.
  • Assessment of tumor suppression and metastasis in vivo.

Main Results:

  • DHODH inhibition decreases cancer cell proliferation by inducing replication and ribosomal stress, dependent on p53 and Chk1.
  • Combined DHODH and Chk1 inhibition leads to aberrant cell cycle re-entry and mitotic errors in p53-dysfunctional cells.
  • This combination therapy effectively suppresses p53-mutated tumors and reduces metastasis.

Conclusions:

  • Targeting DHODH, particularly in combination with Chk1 inhibition, is a promising strategy for treating p53-mutated cancers.
  • The p53 and Chk1 pathways are critical mediators of the anti-cancer effects of DHODH inhibition.

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