Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Cancer Lett. 2019 Apr 28;448:70-83. doi: 10.1016/j.canlet.2019.02.003. Epub 2019 Feb 13.
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.
蛋白酶体抑制剂通过触发急性蛋白毒性应激反应，导致多聚泛素化蛋白积累、内质网应激和活性氧产生，从而诱导癌细胞死亡。聚集物途径已被描述为一种逃避蛋白毒性的机制，通过隔离毒性细胞聚集物。在这里，我们表明，小分子蛋白酶体去泛素化酶活性抑制剂 b-AP15 在没有聚集物形成的情况下诱导多聚泛素积累。发现 b-AP15 会影响处理细胞中的细胞器运输，这增加了这样一种可能性，即有毒蛋白聚集物的微管运输被抑制，导致细胞毒性增强。与临床上使用的蛋白酶体抑制剂硼替佐米的抗增殖作用不同，组蛋白去乙酰化酶抑制剂 SAHA 并不能进一步增强 b-AP15 的作用。我们的结果表明，b-AP15 对错误折叠蛋白的运输具有抑制作用，导致聚集物形成缺乏，并产生强烈的蛋白毒性应激反应。
