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Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
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2019 (Engelska)Ingår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 448, s. 70-83Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Proteasome inhibitors have been shown to induce cell death in cancer cells by triggering an acute proteotoxic stress response characterized by accumulation of poly-ubiquitinated proteins, ER stress and the production of reactive oxygen species. The aggresome pathway has been described as an escape mechanism from proteotoxicity by sequestering toxic cellular aggregates. Here we show that b-AP15, a small-molecule inhibitor of proteasomal deubiquitinase activity, induces poly-ubiquitin accumulation in absence of aggresome formation. b-AP15 was found to affect organelle transport in treated cells, raising the possibility that microtubule-transport of toxic protein aggregates is inhibited, leading to enhanced cytotoxicity. In contrast to the antiproliferative effects of the clinically used proteasome inhibitor bortezomib, the effects of b-AP15 are not further enhanced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Our results suggest an inhibitory effect of b-AP15 on the transport of misfolded proteins, resulting in a lack of aggresome formation, and a strong proteotoxic stress response.

Ort, förlag, år, upplaga, sidor
ELSEVIER IRELAND LTD , 2019. Vol. 448, s. 70-83
Nyckelord [en]
Ubiquitin-proteasome system; Deubiquitinase; UPS inhibitor
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:liu:diva-156592DOI: 10.1016/j.canlet.2019.02.003ISI: 000463129800008PubMedID: 30768956OAI: oai:DiVA.org:liu-156592DiVA, id: diva2:1315592
Anmärkning

Funding Agencies|Radiumhemmets Forskningsfonder [154193]; Cancerfonden [15 0818]; Vetenskapsradet [2015-02905]; Barncancerfonden [2015-0091]; Knut och Alice Wallenbergs Stiftelse [2015.0063]

Tillgänglig från: 2019-05-14 Skapad: 2019-05-14 Senast uppdaterad: 2019-06-28

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Mofers, ArjanSelvaraj, KarthikLinder, StigD´arcy, Padraig
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Avdelningen för läkemedelsforskningMedicinska fakulteten
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Cancer Letters
Cancer och onkologi

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