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

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Title: Molecular mechanism of Forkhead box M1 inhibition by thiostrepton in breast cancer cells
Authors: Kongsema, M
Wongkhieo, S
Khongkow, M
Lam, E
Boonnoy, P
Vongsangnak, W
Wong-Ekkabut, J
Item Type: Journal Article
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.
Issue Date: Sep-2019
Date of Acceptance: 3-Jul-2019
URI: http://hdl.handle.net/10044/1/70737
DOI: 10.3892/or.2019.7225
ISSN: 1021-335X
Publisher: Spandidos Publications
Start Page: 953
End Page: 962
Journal / Book Title: Oncology Reports
Volume: 42
Issue: 3
Copyright Statement: © Kongsema et al. This is an open access article distributed under the terms of Creative Commons Attribution License ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).
Sponsor/Funder: Royal Thai Embassy
Breast Cancer Care & Breast Cancer Now
Breast Cancer Care & Breast Cancer Now
Medical Research Council (MRC)
Funder's Grant Number: WSCC_P37917
Keywords: 1112 Oncology and Carcinogenesis
Publication Status: Published
Online Publication Date: 2019-07-08
Appears in Collections:Department of Surgery and Cancer