Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growthviatargeting proteasome-associated deubiquitinases

// Chong Zhao 1, 2, * , Xin Chen 1, * , Changshan Yang 1, * , Dan Zang 1 , Xiaoying Lan 1 , Siyan Liao 1 , Peiquan Zhang 1 , Jinjie Wu 1 , Xiaofen Li 1 , Ningning Liu 1, 3 , Yuning Liao 1 , Hongbiao Huang 1 , Xianping Shi 1 , Lili Jiang 1 , Xiuhua Liu 4 , Q. Ping Dou 5 , Xuejun Wang 1, 6 , Jinbao Liu 1 1 State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China 2 Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, China 3 Guangzhou Research Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China 4 Institute of Environmental and Analytical Sciences, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, Henan 475004, China 5 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 6 Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota 57069, USA * These authors have contributed equally to this work Correspondence to: Jinbao Liu, email: jliu@gzhmu.edu.cn Xuejun Wang, email: xuejun.wang@usd.edu Keywords: zinc pyrithione, proteasome, deubiquitinases, DNA damage, tumor Received: November 08, 2016 Accepted: December 27, 2016 Published: January 10, 2017 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.