Jump to main content
Jump to site search

Issue 3, 2014
Previous Article Next Article

Identification of an inhibitor of the ubiquitin–proteasome system that induces accumulation of polyubiquitinated proteins in the absence of blocking of proteasome function

Author affiliations

Abstract

The ubiquitin–proteasome system (UPS) represents one of the most promising therapeutic targets in oncology to emerge in recent years. Here we used a combination of cytotoxic and image-based screening assays to identify a novel UPS inhibitor, designated HRF-3. HRF-3 evokes a gene expression profile similar to that of other characterized UPS inhibitors, suggesting a common mechanism of action. Consistent with UPS inhibition, HRF-3 induced strong accumulation of polyubiquitinated proteins in cells. Surprisingly, HRF-3 induced only weak accumulation of two proteasome targeted reporter proteins, UbG76V-YFP and ZsGreen-ODC. Consistent with this observation, HRF-3 did not inhibit proteasome proteolytic activity in an in vitro assay. Similar to a number of other UPS inhibitors, HRF-3 increased the expression of the redox-inducible protein Hmox-1. In distinction to the 20S inhibitor bortezomib, but similarly to two different p97/VCP inhibitors, HRF-3 did not elicit strong induction of the chaperone Hsp70B′. Finally, we show that HRF-3 is cytotoxic to a variety of cancer cell lines and ex vivo patient tumour cells, with the strongest activity observed in cells of leukemic/myeloma origin. Taken together our data show that HRF-3 induces polyubiquitin accumulation in the absence of efficient proteasomal blocking, and suggest that induction of oxidative stress is a common denominator of UPS inhibitors.

Graphical abstract: Identification of an inhibitor of the ubiquitin–proteasome system that induces accumulation of polyubiquitinated proteins in the absence of blocking of proteasome function

Back to tab navigation

Publication details

The article was received on 17 Dec 2013, accepted on 28 Dec 2013 and first published on 09 Jan 2014


Article type: Concise Article
DOI: 10.1039/C3MD00386H
Author version
available:
Download author version (PDF)
Citation: Med. Chem. Commun., 2014,5, 376-385
  • Open access: Creative Commons BY-NC license
  •   Request permissions

    Identification of an inhibitor of the ubiquitin–proteasome system that induces accumulation of polyubiquitinated proteins in the absence of blocking of proteasome function

    C. Haglund, C. Mohanty, M. Fryknäs, P. D'Arcy, R. Larsson, S. Linder and L. Rickardson, Med. Chem. Commun., 2014, 5, 376
    DOI: 10.1039/C3MD00386H

    This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material and it is not used for commercial purposes.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
    • For reproduction of material from PCCP:
      [Original citation] - Published by the PCCP Owner Societies.
    • For reproduction of material from PPS:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
    • For reproduction of material from all other RSC journals:
      [Original citation] - Published by The Royal Society of Chemistry.

    Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.

Search articles by author

Spotlight

Advertisements