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Ciclopirox inhibits cancer cell proliferation by suppression of Cdc25A

Tao Shen1,2, Chaowei Shang1,2, Hongyu Zhou1

  • 1Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.

Genes & Cancer
|July 7, 2017
PubMed

Insights

Ciclopirox olamine (CPX), an anticancer agent, inhibits tumor cell proliferation by promoting the degradation of Cdc25A protein. This mechanism involves increased phosphorylation of Cdc25A, leading to cell cycle arrest.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ciclopirox olamine (CPX), an established fungicide, is a newly recognized anticancer agent.
  • The precise molecular mechanisms driving CPX's anticancer effects require further investigation.

Purpose of the Study:

  • To elucidate the molecular mechanism by which CPX inhibits tumor cell proliferation.
  • To investigate the role of Cdc25A protein in CPX-mediated anticancer activity.

Main Methods:

  • Assessing CPX's impact on Cdc25A protein levels, mRNA, and synthesis in tumor cells.
  • Analyzing CPX-induced changes in G1-cyclin dependent kinases (CDKs) phosphorylation.
  • Investigating the role of Cdc25A phosphorylation at specific sites (S76 and S82) in CPX sensitivity using mutants.
  • Evaluating the effect of Cdc25A-S82A mutant expression on CPX-induced cell proliferation inhibition.

Main Results:

  • CPX significantly reduces Cdc25A protein levels without affecting its mRNA or synthesis, indicating promotion of protein degradation.
  • CPX treatment leads to increased inhibitory phosphorylation of G1-CDKs.
  • CPX enhances Cdc25A phosphorylation at S76 and S82 residues.
  • A Cdc25A-S82A mutant exhibits resistance to CPX-induced degradation, and its ectopic expression partially confers resistance to CPX's antiproliferative effects.

Conclusions:

  • CPX inhibits tumor cell proliferation, at least partially, by inducing Cdc25A protein degradation.
  • The phosphorylation of Cdc25A at S82 is critical for CPX-induced degradation and subsequent inhibition of cell proliferation.
Keywords:
Cdc25ACiclopiroxcell cyclecell proliferationcyclin dependent kinase

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