Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth
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Ningning Liu1,2,*, Xiaofen Li1,*, Hongbiao Huang1,*, Chong Zhao1,*, Siyan Liao1,*, Changshan Yang1,*, Shouting Liu1,*, Wenbin Song1, Xiaoyu Lu1, Xiaoying Lan1, Xin Chen1, Songgang Yi1, Li Xu1,3, Lili Jiang1, Canguo Zhao1, Xiaoxian Dong1, Ping Zhou1, Shujue Li1,4, Shunqing Wang1, Xianping Shi1, Ping Q. Dou1,5, Xuejun Wang1,6, and Jinbao Liu1
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
Jinbao Liu, email:
Keywords: cancer, deubiquitinase, proteasome, auranofin
Received: April 7, 2014 Accepted: June 17, 2014 Published: June 18, 2014
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.
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