Inhibition of proteasome deubiquitinating activity as a new cancer therapy

Pádraig D'Arcy, Slavica Brnjic, Maria Hägg Olofsson, Mårten Fryknäs, Kristina Lindsten, Michelandrea De Cesare, Paola Perego, Behnam Sadeghi, Moustapha Hassan, Rolf Larsson, Stig Linder

Research output: Contribution to journalArticlepeer-review

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 1,2. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target 3. 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.

Original languageEnglish
Pages (from-to)1636-1640
Number of pages5
JournalNature Medicine
Volume17
Issue number12
DOIs
Publication statusPublished - Dec 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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