Oncotarget 2014-07-30

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

Ningning Liu, Xiaofen Li, Hongbiao Huang, Chong Zhao, Siyan Liao, Changshan Yang, Shouting Liu, Wenbin Song, Xiaoyu Lu, Xiaoying Lan, Xin Chen, Songgang Yi, Li Xu, Lili Jiang, Canguo Zhao, Xiaoxian Dong, Ping Zhou, Shujue Li, Shunqing Wang, Xianping Shi, Ping Q Dou, Xuejun Wang, Jinbao Liu

Index: Oncotarget 5(14) , 5453-71, (2014)

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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.