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Publication Detail
Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Kwok JMM, Myatt SS, Marson CM, Coombes RC, Constantinidou D, Lam EWF
  • Publisher:
    AMER ASSOC CANCER RESEARCH
  • Publication date:
    07/2008
  • Pagination:
    2022, 2032
  • Journal:
    MOL CANCER THER
  • Volume:
    7
  • Issue:
    7
  • Print ISSN:
    1535-7163
  • Language:
    EN
  • Keywords:
    TRANSCRIPTION FACTOR, NUCLEAR TRANSLOCATION, FOXM1, FOXO3A, PROGRESSION, CARCINOMAS, PATHWAY, BINDING, GENE, RNA
  • Addresses:
    Lam, EWF
    Univ London Imperial Coll Sci Technol & Med
    Canc Res UK Labs
    Dept Oncol
    London
    W12 0NN
    England
Abstract
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 FOXM 1 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, 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, Delta N-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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