Journal
CANCER LETTERS
Volume 448, Issue -, Pages 70-83Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.02.003
Keywords
Ubiquitin-proteasome system; Deubiquitinase; UPS inhibitor
Categories
Funding
- Radiumhemmets Forskningsfonder [154193]
- Cancerfonden [15 0818]
- Vetenskapsradet [2015-02905]
- Barncancerfonden [2015-0091]
- Knut och Alice Wallenbergs Stiftelse [2015.0063]
- Swedish Research Council [2015-02905] Funding Source: Swedish Research Council
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available