Molecular mechanism of Forkhead box M1 inhibition by thiostrepton in breast cancer cells

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Mesayamas Kongsema1, Sudtirak Wongkhieo1, Mattaka Khongkow2

  • 1Department of Zoology, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.

Oncology Reports
|July 20, 2019
PubMed

Insights

Thiostrepton inhibits the FOXM1 protein, a key factor in breast cancer chemotherapy resistance. This natural antibiotic shows promise in overcoming drug resistance and developing new breast cancer treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Breast cancer is a leading malignancy in women globally.
  • Chemotherapy resistance is a major challenge in treating metastatic breast cancer.
  • The FOXM1 transcription factor promotes DNA repair, contributing to chemotherapy resistance.

Purpose of the Study:

  • To investigate thiostrepton as an inhibitor of the FOXM1 protein in breast cancer.
  • To evaluate thiostrepton's effectiveness in downregulating FOXM1 and inducing cancer cell death.

Main Methods:

  • Cell viability assays to determine thiostrepton's cytotoxicity.
  • Quantitative analysis of FOXM1 mRNA and its downstream target CCNB1.
  • Molecular docking and dynamic simulations to elucidate drug-protein-DNA interactions.

Main Results:

  • Thiostrepton effectively downregulated FOXM1 mRNA expression and activity.
  • Treatment with thiostrepton led to breast cancer cell senescence and apoptosis.
  • Thiostrepton decreased the expression of CCNB1, a FOXM1 target gene.
  • Molecular simulations revealed thiostrepton binds to FOXM1 and DNA, inhibiting its function.

Conclusions:

  • Thiostrepton is a specific and direct inhibitor of the FOXM1 protein in breast cancer.
  • This study provides a basis for novel therapeutic strategies to overcome chemotherapy resistance in breast cancer.

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