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Niclosamide exerts anticancer effects through inhibition of the FOXM1-mediated DNA damage response in prostate cancer

Mee Young Kim1,2, Ae Ryang Jung1,2, Dongho Shin1

  • 1Department of Urology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul 06591, Republic of Korea.

American Journal of Cancer Research
|July 12, 2021
PubMed

Insights

Niclosamide, an anti-helminthic drug, shows anticancer effects in castration-resistant prostate cancer (CRPC) by inhibiting the FOXM1-mediated DNA damage response, reducing tumor growth and cell proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Niclosamide is an anti-helminthic drug with demonstrated anticancer properties against various cancers.
  • The precise mechanisms underlying niclosamide's anticancer activity, particularly in prostate cancer, remain largely undefined.
  • Castration-resistant prostate cancer (CRPC) presents a significant clinical challenge requiring novel therapeutic strategies.

Purpose of the Study:

  • To investigate the anticancer effects of niclosamide in CRPC cells.
  • To elucidate the molecular mechanisms through which niclosamide exerts its effects in CRPC.
  • To identify key molecular targets and pathways involved in niclosamide's anti-CRPC action.

Main Methods:

  • In vitro and in vivo studies using CRPC cell lines and xenograft models.
  • Assessment of cell proliferation, apoptosis, and DNA damage markers (γH2AX, 53BP1).
  • RNA-sequencing and bioinformatics analysis (TCGA dataset) to identify gene expression changes and molecular targets, including FOXM1.
  • Microarray assays and luciferase reporter assays to validate the role of FOXM1 and its interaction with DNA repair genes like EXO1.

Main Results:

  • Niclosamide significantly inhibited CRPC cell proliferation and induced apoptosis in vitro.
  • Niclosamide reduced tumor growth in vivo and increased markers of DNA damage.
  • RNA-sequencing revealed niclosamide-induced alterations in genes related to cell division, DNA replication, and repair.
  • FOXM1 was identified as a key target, with its knockdown impairing DNA repair and homologous recombination.
  • FOXM1 was shown to bind to EXO1, and its knockdown reduced EXO1-driven activity.

Conclusions:

  • Niclosamide demonstrates significant anticancer efficacy against castration-resistant prostate cancer.
  • The mechanism involves the inhibition of the FOXM1-mediated DNA damage response pathway.
  • Targeting the FOXM1-DNA repair axis represents a potential therapeutic strategy for CRPC.
Keywords:
Castration-resistant prostate cancerDNA damage responseEXO1FOXM1niclosamide

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