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Molecular mechanism of Forkhead box M1 inhibition by thiostrepton in breast cancer cells
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Document Title
Molecular mechanism of Forkhead box M1 inhibition by thiostrepton in breast cancer cells
Author
Kongsema M.,Wongkhieo S.,Khongkow M.,Lam E.W.-F.,Boonnoy P.,Vongsangnak W.,Wong-Ekkabut J.
Name from Authors Collection
Affiliations
Department of Zoology, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand; Computational Biomodelling Laboratory for Agricultural Science and Technology (CBLAST), Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand; Thailand Center of Excellence in Physics (ThEP Center), Commission on Higher Education, Bangkok, 10400, Thailand; National Nanotechnology Centre (NANOTEC), National Science and Technology Development Agency, Pathum Thani, 12120, Thailand; Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, United Kingdom; Department of Physics, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand; Specialized Center of Rubber and Polymer Materials for Agriculture and Industry (RPM), Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand
Type
Article
Source Title
Oncology Reports
ISSN
1021335X
Year
2019
Volume
42
Issue
3
Open Access
All Open Access, Hybrid Gold, Green
Publisher
Spandidos Publications
DOI
10.3892/or.2019.7225
Abstract
Breast cancer is the most common type of malignancies in women worldwide, and genotoxic chemotherapeutic drugs are effective by causing DNA damage in cancer cells. However, >90% of patients with metastatic cancer are resistant to chemotherapy. The Forkhead box M1 (FOXM1) transcription factor plays a pivotal role in the resistance of breast cancer cells to chemotherapy by promoting DNA damage repair following genotoxic drug treatment. The aim of the present study was to investigate the inhibition of the FOXM1 protein by thiostrepton, a natural antibiotic produced by the Streptomyces species. Experimental studies were designed to examine the effectiveness of thiostrepton in downregulating FOXM1 mRNA expression and activity, leading to senescence and apoptosis of breast cancer cells. The cytotoxicity of thiostrepton in breast cancer was determined using cell viability assay. Additionally, thiostrepton treatment decreased the mRNA expression of cyclin B1 (CCNB1), a downstream target of FOXM1. The present results indicated that thiostrepton inhibited FOXM1 mRNA expression and its effect on CCNB1. Molecular dynamic simulations were performed to study the interactions between FOXM1.DNA and thiostrepton after molecular docking. The results revealed that the possible mechanism underlying the inhibitory effect of thiostrepton on FOXM1 function was by forming a tight complex with the DNA and FOXM1 via its binding domain. Collectively, these results indicated that thiostrepton is a specific and direct inhibitor of the FOXM1 protein in breast cancer. The findings of the present study may lead to the development of novel therapeutic strategies for breast cancer and help overcome resistance to conventional chemotherapeutic drugs. © 2019 Spandidos Publications. All rights reserved.
Industrial Classification
Knowledge Taxonomy Level 1
Knowledge Taxonomy Level 2
Knowledge Taxonomy Level 3
Funding Sponsor
Breast Cancer Now; Manchester Biomedical Research Centre; Medical Research Council; National Institute for Health Research; Cancer Research UK; Thailand Research Fund; Kasetsart University; National Research Council of Thailand; Kasetsart University Research and Development Institute; Thailand Graduate Institute of Science and Technology; NIHR Imperial Biomedical Research Centre
License
CC BY-NC-ND
Rights
Author
Publication Source
Scopus