Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression

Cancer Research-UK Labs, Department of Oncology, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.
Molecular Cancer Therapeutics (Impact Factor: 5.68). 07/2008; 7(7):2022-32. DOI: 10.1158/1535-7163.MCT-08-0188
Source: PubMed


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.

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Available from: Eric W-F Lam, Dec 30, 2015
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    • "The fact that this effect is only seen in cancer cells, but not in non-malignant cells, indicates that cancer cells are addicted to FOXM1 overexpression [82] [83]. Furthermore, breast cancer cells treated with thiostrepton also become less migratory and invasive [82]. The exact mechanism of action of both thiostrepton and Siomycin A is unclear, but could be related to their ability to bind to the FKH DNA-binding domain of FOXM1, thereby preventing FOXM1 from binding to its target genes [84]. "
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    • "To test if FOXM1 inactivation is a viable strategy for overcoming docetaxel resistance, we studied the effects of AGS-DOCR cells treated with FOXM1 inhibitor thiostrepton [30]. In result, MTT assays revealed that docetaxel resistant cells exhibited a significant reduction in the rate of cell viability after treated with thiostrepton or in combination with docetaxel compared with the single treatment of docetaxel. "
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    • "A number of studies have demonstrated overexpression of the FoxM1 gene in human cancer cells and tissues, including in ovarian cancer (32,33,37,38), and emerging evidence suggests that the inactivation of FoxM1 may have important implications in cancer therapy. For example, it may be possible to downregulate FoxM1 expression using specific drugs, such as siomycin A, thiostrepton and the epidermal growth factor receptor (EGFR) inhibitor gefitinib (27,39,40). Wang et al demonstrated that genistein is capable of inhibiting FoxM1 activation in pancreatic cancer cells, leading to cell growth inhibition and the induction of apoptosis (32). "
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