Abstract
Forkhead box M1 (FoxM1) oncogenic transcription factor represents an attractive therapeutic target in the fight against cancer, because it is overexpressed in a majority of human tumors. Recently, using a cell-based assay system we identified thiazole antibiotic Siomycin A as an inhibitor of FoxM1 transcriptional activity. Here, we report that structurally similar thiazole antibiotic, thiostrepton also inhibits the transcriptional activity of FoxM1. Furthermore, we found that these thiopeptides did not inhibit the transcriptional activity of other members of the Forkhead family or some non-related transcription factors. Further experiments revealed that thiazole antibiotics also inhibit FoxM1 expression, but not the expression of other members of the Forkhead box family. In addition, we found that the thiazole antibiotics efficiently inhibited the growth and induced potent apoptosis in human cancer cell lines of different origin. Thiopeptide-induced apoptosis correlated with the suppression of FoxM1 expression, while overexpression of FoxM1 partially protected cancer cells from the thiazole antibiotic-mediated cell death. These data suggest that Siomycin A and thiostrepton may specifically target FoxM1 to induce apoptosis in cancer cells and FoxM1 inhibitors/thiazole antibiotics could be potentially developed as novel anticancer drugs against human neoplasia.
Highlights
Forkhead box M1 (FoxM1) [1], a transcription factor of the Forkhead family [2] is one of the key positive regulators of the cell cycle
To evaluate the effects of thiostrepton on FoxM1 transcriptional activity and to study how the thiazole antibiotics affect the transcriptional activity of other members of the Forkhead family, we developed the C3Luc2.3-FoxO1 cell line
To test how thiostrepton affects FoxM1 transcriptional activity compared to Siomycin A, cells were treated with a combination of doxycycline and the thiazole antibiotics and 16 hours later the luciferase activity was measured
Summary
Forkhead box M1 (FoxM1) [1], a transcription factor of the Forkhead family [2] is one of the key positive regulators of the cell cycle. Both the expression and the transcriptional activity of FoxM1 is associated with the proliferative state of cells [1]. It is expressed in all embryonic tissues and in proliferating cells of epithelial and mesenchymal origin [3,4]. FoxM1 transcriptionally upregulates target genes involved in cell cycle progression and it is critical for G1/S and G2/M transition, and for the execution of the mitotic program because FoxM1-depleted cells fail to advance beyond the prophase stage of mitosis [10]
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