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

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 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, #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.

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

“…Our studies and various previous studies (58,59) indicated that this antibiotic also exhibits inhibitory activity against the proteasome. Although its applications with respect to autoimmune disorders have never been investigated, antitumor effects of thiostrepton have been reported.…”

“…Although its applications with respect to autoimmune disorders have never been investigated, antitumor effects of thiostrepton have been reported. For example, thiostrepton was found to exhibit anti-breast cancer cell activity by inhibiting proteasome activity and consequently controlling the transcriptional activity of FOXM1 (37,58,59).…”

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

“…Cell cycle analysis was done by propidium iodide staining, as previously described (29). Both adherent and floating cells were harvested and stained with propidium iodide (0.2 mg/mL) in the presence of DNasefree RNase for flow cytometry analysis.…”

Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system

“…This interaction inhibits translation and also synthesis of the global gene expression regulator (p)ppGpp (40,41). Furthermore, thiostrepton inhibits the proteasome in eukaryotic cells (42,43) exerting antimalarial (44,45) and anticancer (42)(43)(44)(45)(46)(47) activities. Despite their unique mechanism of action and their high potency against pathogens such as methicillin-resistant Staphylococcus aureus and Enterococcus faecium or penicillin-resistant Streptococcus pneumonia (48), the clinical application of thiopeptides is impeded by their considerable size and low water solubility (35,(48)(49)(50)(51).…”