title: Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases.
abstract: The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activity are currently in clinical use for treatment of multiple myeloma and other cancers, and the deubiquitinase activity associated with the proteasome is also a valid target for anticancer agents. Recent studies suggested that zinc pyrithione, an FDA-approved antidandruff agent, may have antitumor activity, but the detailed molecular mechanisms remain unclear. Here we report that zinc pyrithione (ZnPT) targets the proteasome-associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes. Furthermore, ZnPT exhibits cytotoxic effects against various cancer cell lines in vitro, selectively kills bone marrow cells from leukemia patients ex vivo, and efficiently inhibits the growth of lung adenocarcinoma cancer cell xenografts in nude mice. This study has identified zinc pyrithione, an FDA-approved pharmacological agent with potential antitumor properties as a proteasomal DUB inhibitor.
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.|Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Changshan
authors.initials: C
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zang
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Lan
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Siyan
authors.initials: S
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Peiquan
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Jinjie
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.|Guangzhou Research Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xianping
authors.initials: X
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, Henan 475004, China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Liu
authors.affiliation: 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 Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.|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: State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, 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*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D063807:Dandruff / Q000188:drug therapy; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007641:Keratolytic Agents / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000473:pathology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007641:Keratolytic Agents; D009942:Organometallic Compounds; D061988:Proteasome Inhibitors; D011725:Pyridines; C509299:USP14 protein, human; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex; C010423:pyrithione zinc
keywords: DNA damage; deubiquitinases; proteasome; tumor; zinc pyrithione