Abstract
Proteasome inhibitors are currently in the clinic or in clinical trials, but the mechanism of their anticancer activity is not completely understood. The oncogenic transcription factor FoxM1 is one of the most overexpressed genes in human tumors, while its expression is usually halted in normal non-proliferating cells. Previously, we established that thiazole antibiotics Siomycin A and thiostrepton inhibit FoxM1 and induce apoptosis in human cancer cells. Here, we report that Siomycin A and thiostrepton stabilize the expression of a variety of proteins, such as p21, Mcl-1, p53 and hdm-2 and also act as proteasome inhibitors in vitro. More importantly, we also found that well-known proteasome inhibitors such as MG115, MG132 and bortezomib inhibit FoxM1 transcriptional activity and FoxM1 expression. In addition, overexpression of FoxM1 specifically protects against bortezomib-, but not doxorubicin-induced apoptosis. These data suggest that negative regulation of FoxM1 by proteasome inhibitors is a general feature of these drugs and it may contribute to their anticancer properties.
Highlights
The proteasome is a protein complex that target ubiquitintagged proteins for degradation in an ATP-dependent manner
In our previous studies we demonstrated that thiazole antibiotics Siomycin A and thiostrepton induce apoptosis in human cancer cells and inhibit FoxM1 expression [13,17,18]
We showed that well-known proteasome inhibitors such as MG115, MG132 or Bortezomib inhibit FoxM1 transcriptional activity and expression
Summary
The proteasome is a protein complex that target ubiquitintagged proteins for degradation in an ATP-dependent manner. In our previous studies we demonstrated that thiazole antibiotics Siomycin A and thiostrepton induce apoptosis in human cancer cells and inhibit FoxM1 expression [13,17,18]. We showed that well-known proteasome inhibitors such as MG115, MG132 or Bortezomib inhibit FoxM1 transcriptional activity and expression.
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