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Inhibition of proteasome deubiquitinating activity as a new cancer therapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
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2011 (English)In: Nature Medicine, ISSN 1078-8956, Vol. 17, no 12, 1636-1640 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2011. Vol. 17, no 12, 1636-1640 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-165653DOI: 10.1038/nm.2536ISI: 000297978000035OAI: oai:DiVA.org:uu-165653DiVA: diva2:475185
Available from: 2012-01-10 Created: 2012-01-09 Last updated: 2012-03-15Bibliographically approved

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Fryknäs, MårtenLarsson, Rolf
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