Department of Zoology, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
National Nanotechnology Centre (NANOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
Oncol Rep. 2019 Sep;42(3):953-962. doi: 10.3892/or.2019.7225. Epub 2019 Jul 8.
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.
乳腺癌是全球女性中最常见的恶性肿瘤类型，细胞毒性化疗药物通过在癌细胞中引起 DNA 损伤而有效。然而，>90%的转移性癌症患者对化疗有耐药性。叉头框 M1（FOXM1）转录因子在乳腺癌细胞对化疗的耐药性中发挥关键作用，通过在基因毒性药物治疗后促进 DNA 损伤修复。本研究旨在研究由链霉菌属产生的天然抗生素硫链丝菌素对 FOXM1 蛋白的抑制作用。实验研究旨在研究硫链丝菌素下调 FOXM1 mRNA 表达和活性、导致乳腺癌细胞衰老和凋亡的有效性。使用细胞活力测定法测定硫链丝菌素对乳腺癌的细胞毒性。此外，硫链丝菌素处理降低了 FOXM1 的下游靶标细胞周期蛋白 B1（CCNB1）的 mRNA 表达。本研究结果表明，硫链丝菌素抑制 FOXM1 mRNA 表达及其对 CCNB1 的作用。进行分子动力学模拟以研究分子对接后 FOXM1-DNA 和硫链丝菌素之间的相互作用。结果表明，硫链丝菌素抑制 FOXM1 功能的可能机制是通过其结合域与 DNA 和 FOXM1 形成紧密复合物。总之，这些结果表明硫链丝菌素是乳腺癌中 FOXM1 蛋白的特异性和直接抑制剂。本研究的结果可能为乳腺癌的新型治疗策略的发展提供依据，并有助于克服对传统化疗药物的耐药性。
