Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth

Abstract

// Ningning Liu 1,2,* , Xiaofen Li 1,* , Hongbiao Huang 1,* , Chong Zhao 1,* , Siyan Liao 1,* , Changshan Yang 1,* , Shouting Liu 1,* , Wenbin Song 1 , Xiaoyu Lu 1 , Xiaoying Lan 1 , Xin Chen 1 , Songgang Yi 1 , Li Xu 1,3 , Lili Jiang 1 , Canguo Zhao 1 , Xiaoxian Dong 1 , Ping Zhou 1 , Shujue Li 1,4 , Shunqing Wang 1 , Xianping Shi 1 , Ping Q. Dou 1,5 , Xuejun Wang 1,6 , and Jinbao Liu 1 1 State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China 2 Guangzhou Research Institute of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China 3 Department of Hematology, The People’s Hospital of Guangxi Autonomous Region, Nanning, Guangxi, People’s Republic of China 4 Guangzhou Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of 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, USA 6 Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota, USA * These Authors contributed equally to this work Correspondence: Jinbao Liu, email: // Keywords : cancer, deubiquitinase, proteasome, auranofin Received : April 7, 2014 Accepted : June 17, 2014 Published : June 18, 2014 Abstract Proteasomes are attractive emerging targets for anti-cancer therapies. Auranofin (Aur), a gold-containing compound clinically used to treat rheumatic arthritis, was recently approved by US Food and Drug Administration for Phase II clinical trial to treat cancer but its anti-cancer mechanism is poorly understood. Here we report that (i) Aur shows proteasome-inhibitory effect that is comparable to that of bortezomib/Velcade (Vel); (ii) different from bortezomib, Aur inhibits proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14 rather than the 20S proteasome; (iii) inhibition of the proteasome-associated DUBs is required for Aur-induced cytotoxicity; and (iv) Aur selectively inhibits tumor growth in vivo and induces cytotoxicity in cancer cells from acute myeloid leukemia patients. This study provides important novel insight into understanding the proteasome-inhibiting property of metal-containing compounds. Although several DUB inhibitors were reported, this study uncovers the first drug already used in clinic that can inhibit proteasome-associated DUBs with promising anti-tumor effects.