Kwok Jimmy M-M, Myatt Stephen S, Marson Charles M, Coombes R Charles, Constantinidou Demetra, Lam Eric W-F
Cancer Research-UK Labs, Department of Oncology, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.
Mol Cancer Ther. 2008 Jul;7(7):2022-32. doi: 10.1158/1535-7163.MCT-08-0188.
Elevated expression or activity of the transcription factor forkhead box M1 (FOXM1) is associated with the development and progression of many malignancies, including breast cancer. In this study, we show that the thiazole antibiotic thiostrepton selectively induces cell cycle arrest and cell death in breast cancer cells through down-regulating FOXM1 expression. Crucially, our data show that thiostrepton treatment reduced FOXM1 expression in a time- and dose-dependent manner, independent of de novo protein synthesis and predominantly at transcriptional and gene promoter levels. Our results indicate that thiostrepton can induce cell death through caspase-dependent intrinsic and extrinsic apoptotic pathways as well as through caspase-independent death mechanisms, as observed in MCF-7 cells, which are deficient of caspase-3 and caspase-7. Cell cycle analysis showed that thiostrepton induced cell cycle arrest at G(1) and S phases and cell death, concomitant with FOXM1 repression in breast cancer cells. Furthermore, thiostrepton also shows efficacy in repressing breast cancer cell migration, metastasis, and transformation, which are all downstream functional attributes of FOXM1. We also show that overexpression of a constitutively active FOXM1 mutant, DeltaN-FOXM1, can abrogate the antiproliferative effects of thiostrepton. Interestingly, thiostrepton has no affect on FOXM1 expression and proliferation of the untransformed MCF-10A breast epithelial cells. Collectively, our data show that FOXM1 is one of the primary cellular targets of thiostrepton in breast cancer cells and that thiostrepton may represent a novel lead compound for targeted therapy of breast cancer with minimal toxicity against noncancer cells.
转录因子叉头框M1（FOXM1）的表达升高或活性增强与包括乳腺癌在内的多种恶性肿瘤的发生和发展相关。在本研究中，我们发现噻唑类抗生素硫链丝菌素可通过下调FOXM1表达，选择性地诱导乳腺癌细胞的细胞周期停滞和细胞死亡。至关重要的是，我们的数据表明，硫链丝菌素处理以时间和剂量依赖性方式降低FOXM1表达，这与从头蛋白质合成无关，且主要发生在转录和基因启动子水平。我们的结果表明，硫链丝菌素可通过半胱天冬酶依赖性的内源性和外源性凋亡途径以及通过半胱天冬酶非依赖性死亡机制诱导细胞死亡，如在缺乏半胱天冬酶-3和半胱天冬酶-7的MCF-7细胞中所观察到的。细胞周期分析表明，硫链丝菌素诱导乳腺癌细胞在G(1)期和S期发生细胞周期停滞并导致细胞死亡，同时伴有FOXM1的抑制。此外，硫链丝菌素在抑制乳腺癌细胞迁移、转移和转化方面也显示出效果，而这些都是FOXM1的下游功能特性。我们还表明，组成型活性FOXM1突变体DeltaN-FOXM1的过表达可消除硫链丝菌素的抗增殖作用。有趣的是，硫链丝菌素对未转化的MCF-10A乳腺上皮细胞的FOXM1表达和增殖没有影响。总的来说，我们的数据表明FOXM1是硫链丝菌素在乳腺癌细胞中的主要细胞靶点之一，并且硫链丝菌素可能代表一种新型先导化合物，用于乳腺癌的靶向治疗，对非癌细胞的毒性最小。
