Identification of an inhibitor of the ubiquitin-proteasome system that induces accumulation of polyubiquitinated proteins in the absence of blocking of proteasome function
2014 (English)In: MedChemComm, ISSN 2040-2503, Vol. 5, no 3, 376-385 p.Article in journal (Refereed) Published
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, Ub(G76V)-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.
Place, publisher, year, edition, pages
2014. Vol. 5, no 3, 376-385 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-224143DOI: 10.1039/c3md00386hISI: 000333227000018OAI: oai:DiVA.org:uu-224143DiVA: diva2:715653