A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases

• Published in: Scientific reports 2014-06, Vol.4 (1), p.5240-5240, Article 5240
• Main Authors: Liu, Ningning, Liu, Chunjiao, Li, Xiaofen, Liao, Siyan, Song, Wenbin, Yang, Changshan, Zhao, Chong, Huang, Hongbiao, Guan, Lixia, Zhang, Peiquan, Liu, Shouting, Hua, Xianliang, Chen, Xin, Zhou, Ping, Lan, Xiaoying, Yi, Songgang, Wang, Shunqing, Wang, Xuejun, Dou, Q. Ping, Liu, Jinbao
• Format: Article
• Language: English
• Subjects: 13; 13/2; 13/31; 631/67; 692/308/575; Animals; Antifoulants; Antifouling substances; Antineoplastic Agents - pharmacology; Biocides; Boronic Acids - pharmacology; Bortezomib; Cancer; Cancer therapies; Cell Line; Cell Line, Tumor; Copper; Cytotoxicity; HEK293 Cells; Hep G2 Cells; Humanities and Social Sciences; Humans; Male; Metal complexes; Mice; Mice, Inbred BALB C; Mice, Nude; multidisciplinary; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Organometallic Compounds - pharmacology; Peptide Hydrolases - metabolism; Protease inhibitors; Protease Inhibitors - pharmacology; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; Proteasomes; Proteolysis; Proteolysis - drug effects; Pyrazines - pharmacology; Pyridines - pharmacology; Pyrithione; Science; Tributyltin; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-Specific Proteases - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep05240

The successful development of bortezomib-based therapy for treatment of multiple myeloma has established proteasome inhibition as an effective therapeutic strategy and both 20S proteasome peptidases and 19S deubiquitinases (DUBs) are becoming attractive targets of cancer therapy. It has been reported that metal complexes, such as copper complexes, inhibit tumor proteasome. However, the involved mechanism of action has not been fully characterized. Here we report that (i) copper pyrithione (CuPT), an alternative to tributyltin for antifouling paint biocides, inhibits the ubiquitin-proteasome system (UPS) via targeting both 19S proteasome-specific DUBs and 20S proteolytic peptidases with a mechanism distinct from that of the FDA-approved proteasome inhibitor bortezomib; (ii) CuPT potently inhibits proteasome-specific UCHL5 and USP14 activities; (iii) CuPT inhibits tumor growth in vivo and induces cytotoxicity in vitro and ex vivo . This study uncovers a novel class of dual inhibitors of DUBs and proteasome and suggests a potential clinical strategy for cancer therapy.