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Identification of a...
Identification of an inhibitor of the ubiquitin-proteasome system that induces accumulation of polyubiquitinated proteins in the absence of blocking of proteasome function
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- Haglund, Caroline (författare)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- Mohanty, Chitralekha (författare)
- Karolinska Institutet
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- Fryknäs, Mårten (författare)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- D'Arcy, Padraig (författare)
- Karolinska Institutet
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- Larsson, Rolf (författare)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- Linder, Stig (författare)
- Karolinska Institutet,Uppsala universitet,Institutionen för medicinska vetenskaper
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- Rickardson, Linda (författare)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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(creator_code:org_t)
- 2014
- 2014
- Engelska.
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 5:3, s. 376-385
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https://pubs.rsc.org...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
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