Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles1,2. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target3. Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle–associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2. We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.
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We thank M. Glickman (Department of Biology, Technion-Israel Institute of Technology) for providing the Ub-GFP constructs, N. Dantuma (Department of Cell and Molecular Biology, Karolinska Institutet) for providing the MelJuSo Ub-YFP reporter cell line, B. Vogelstein (Sidney Kimmel Comprehensive Cancer Center, John Hopkins University) for providing the HCT-116 cell lines with targeted disruptions, L. Perup Segerström for technical advice, Uppsala Array Platform and L. Gatti for drug formulation. We thank Cancerfonden, Radiumhemmets forskningsfonder, Vetenskapsrådet, Strategiska forskningsstiftelsen, Vinnova, European Union CHEMORES, Frame Program 6 (LSHC-CT-2007-037665), Lions Cancerforskningsfond and Swedish Children Cancer Society for support.
The authors declare no competing financial interests.
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D'Arcy, P., Brnjic, S., Olofsson, M. et al. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med 17, 1636–1640 (2011) doi:10.1038/nm.2536
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