title: Inhibition of proteasome deubiquitinating activity as a new cancer therapy.
abstract: Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target. 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.
authors: Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
authors: Pádraig
authors: P
authors: D'Arcy
authors: Slavica
authors: S
authors: Brnjic
authors: Maria Hägg
authors: MH
authors: Olofsson
authors: Mårten
authors: M
authors: Fryknäs
authors: Kristina
authors: K
authors: Lindsten
authors: Michelandrea
authors: M
authors: De Cesare
authors: Paola
authors: P
authors: Perego
authors: Behnam
authors: B
authors: Sadeghi
authors: Moustapha
authors: M
authors: Hassan
authors: Rolf
authors: R
authors: Larsson
authors: Stig
authors: S
authors: Linder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D001943:Breast Neoplasms; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D046228:Microarray Analysis; D009101:Multiple Myeloma / Q000188:drug therapy; D010881:Piperidones / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C569633:3,5-bis((4-nitrophenyl)methylidene)-1-prop-2-enoylpiperidin-4-one; D000970:Antineoplastic Agents; D001897:Boronic Acids; D010881:Piperidones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C509299:USP14 protein, human; D025801:Ubiquitin; C469268:Usp14 protein, mouse; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; D002268:Carboxypeptidases; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C119011:26S proteasome non-ATPase regulatory subunit 13