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

Ningning Liu, Chunjiao Liu, Xiaofen Li, Siyan Liao, Wenbin Song, Changshan Yang, Chong Zhao, Hongbiao Huang, Lixia Guan, Peiquan Zhang, Shouting Liu, Xianliang Hua, Xin Chen, Ping Zhou, Xiaoying Lan, Songgang Yi, Shunqing Wang, Xuejun Wang, Q. Ping Dou, Jinbao Liu

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Abstract

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.

Original languageEnglish (US)
Article number5240
JournalScientific reports
Volume4
DOIs
StatePublished - Jun 10 2014

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    Liu, N., Liu, C., Li, X., Liao, S., Song, W., Yang, C., Zhao, C., Huang, H., Guan, L., Zhang, P., Liu, S., Hua, X., Chen, X., Zhou, P., Lan, X., Yi, S., Wang, S., Wang, X., Dou, Q. P., & Liu, J. (2014). A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases. Scientific reports, 4, [5240]. https://doi.org/10.1038/srep05240