Deubiquitinase Inhibitor AuPT Downregulates NF-κB Signaling and Induces Apoptosis via Inhibiting UCHL5 and USP14 in Prostate Cancer

Abstract

Background: Deubiquitinases (DUBs) are essential components of the ubiquitin-proteasome system (UPS) that regulates cancer-related processes. Effective inhibitors of 19S proteasome-associated DUBs, including ubiquitin carboxy-terminal hydrolase L5 (UCHL5), ubiquitin-specific protease 14 (USP14), and gold-(triphenylphosphine (PPh3))-platinum (AuPT), suppress cell growth in several human tumor cell lines. The aim of this study was to determine the effect of AuPT and its mechanism of action on prostate cancer (PCa) progression. Methods: The malignant PCa phenotype and apoptotic cell death were evaluated in vitro. The antitumor activity of AuPT was verified using nude xenografts. Furthermore, the protein levels in the UPS and the phosphorylation of p65 were determined by overexpression plasmid transfection using Western blotting. Results: The viability, invasion, and migration abilities of PCa cells decreased and the cell apoptosis rate increased with AuPT treatment in a time-dependent manner (p < 0.05, p < 0.01). The tumor weight and volume were effectively suppressed in nude mice (p < 0.01). DUB protein expression levels and p65 phosphorylation were downregulated and restored after overexpression of USP14 or UCHL5 (p < 0.05, p < 0.01, p < 0.001). Conclusions: We found that AuPT induced PCa cell apoptosis and inhibited the activation of nuclear factor-κB (NF-κB) signaling by disturbing UPS functioning. AuPT treatment may enable specific targeted therapy against NF-κB-activated PCa.