title: A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases.
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.
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2] Guangzhou Research Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, People's Republic of China [3].
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2].
authors.forename: Chunjiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2].
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2].
authors.forename: Siyan
authors.initials: S
authors.lastname: Liao
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2].
authors.forename: Wenbin
authors.initials: W
authors.lastname: Song
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2].
authors.forename: Changshan
authors.initials: C
authors.lastname: Yang
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2].
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2].
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Guan
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Peiquan
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Shouting
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xianliang
authors.initials: X
authors.lastname: Hua
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Lan
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Songgang
authors.initials: S
authors.lastname: Yi
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Shunqing
authors.initials: S
authors.lastname: Wang
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2] Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota 57069, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China [2] The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201-2013, USA.
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002460:Cell Line; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D009942:Organometallic Compounds; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011725:Pyridines; D025801:Ubiquitin; C487833:copper pyrithione; D000069286:Bortezomib; D010447:Peptide Hydrolases; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex