The ubiquitin-proteasome system is elementary for cellular protein degradation and gained rising attention as a new target for cancer therapy due to promising clinical trials with bortezomib, the first-in class proteasome inhibitor meanwhile approved for multiple myeloma and mantle cell lymphoma. Both bortezomib and next-generation proteasome inhibitors mediate their effects by targeting the 20S core particle of the 26S proteasome. The novel small molecule inhibitor b-AP15 affects upstream elements of the ubiquitin-proteasome cascade by suppressing the deubiquitinase activity of both proteasomal regulatory 19S subunits and showed promising anticancer activity in preclinical models. Nonetheless, effects of inhibitors on the ubiquitin-proteasome system are not exclusively restricted to malignant cells: alteration of natural killer cell-mediated immune responses had already been described for drugs targeting either 19S or 20S proteasomal subunits. Moreover, it has been shown that bortezomib impairs dendritic cell (DC) phenotype and function at different levels. In the present study, we comparatively analyzed effects of bortezomib and b-AP15 on monocyte-derived DCs. In line with previous results, bortezomib exposure impaired maturation, antigen uptake, migration, cytokine secretion and immunostimulation, whereas treatment with b-AP15 had no compromising effects on these DC features. Our findings warrant the further investigation of b-AP15 as an alternative to clinically approved proteasome inhibitors in the therapy of malignancies, especially in the context of combinatorial treatment with DC-based immunotherapies.

中文翻译：

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去泛素酶抑制剂b-AP15及其对单核细胞衍生树突状细胞表型和功能的影响。

泛素-蛋白酶体系统是细胞蛋白质降解的基本要素，由于硼替佐米是一种有前途的临床试验，它已被批准用于多发性骨髓瘤和套细胞淋巴瘤，因此它是癌症治疗的新靶点，因为硼替佐米是一种有前途的临床试验。硼替佐米和下一代蛋白酶体抑制剂均通过靶向26S蛋白酶体的20S核心颗粒来介导其作用。新型小分子抑制剂b-AP15通过抑制两个蛋白酶体调控19S亚基的去泛素酶活性，影响泛素-蛋白酶体级联反应的上游元件，并在临床前模型中显示出有希望的抗癌活性。尽管如此，抑制剂对泛素-蛋白酶体系统的作用并不仅仅局限于恶性细胞：已经针对靶向19S或20S蛋白酶体亚基的药物描述了天然杀伤细胞介导的免疫反应的改变。而且，已经显示硼替佐米在不同水平上损害树突状细胞（DC）表型和功能。在本研究中，我们比较了硼替佐米和b-AP15对单核细胞衍生DC的作用。与以前的结果一致，硼替佐米暴露会损害成熟，抗原摄取，迁移，细胞因子分泌和免疫刺激，而b-AP15的治疗对这些DC功能没有损害作用。我们的发现需要进一步研究b-AP15作为临床批准的蛋白酶体抑制剂在恶性肿瘤治疗中的替代方法，尤其是在基于DC的免疫疗法联合治疗的情况下。