Paradoxical inhibition of cellular protein expression by proteasome inhibitors.

Abstract Proteasome inhibitors are used as anticancer drugs, however, the precise mechanisms of their selective activity against cancer cells are not understood well. While proteasome inhibitors stabilize the majority of cellular proteins through inhibition of proteasome activity, they also paradoxically downregulate several other proteins. We recently discovered that proteasome inhibitors suppress mRNA and protein expression of FOXM1, NPM, and ARF proteins that are involved in cancer. We postulated that proteasome inhibitors preferentially stabilize negative regulators of transcription of these genes, which overrides their protein stabilization. These data suggest a presence of multiple secondary mechanisms that may regulate transcription, degradation, or localization of cellular proteins after treatment with proteasome inhibitors. Future experiments will identify these mechanisms and additional proteins suppressed by proteasome inhibitors, and will help explain the role of protein suppression by proteasome inhibitors in their anticancer activity.