Comprehensive Pneumology Center (CPC), University Hospital of the Ludwig-Maximilians-University (LMU) and Helmholtz Zentrum München, German Center for Lung Research (DZL), 81377 Munich, Germany.
Comprehensive Pneumology Center (CPC), University Hospital of the Ludwig-Maximilians-University (LMU) and Helmholtz Zentrum München, German Center for Lung Research (DZL), 81377 Munich, Germany.
Pharmacol Ther. 2020 Jul;211:107526. doi: 10.1016/j.pharmthera.2020.107526. Epub 2020 Mar 13.
The proteasome is a well-identified therapeutic target for cancer treatment. It acts as the main protein degradation system in the cell and degrades key mediators of cell growth, survival and function. The term "proteasome" embraces a whole family of distinct complexes, which share a common proteolytic core, the 20S proteasome, but differ by their attached proteasome activators. Each of these proteasome complexes plays specific roles in the control of cellular function. In addition, distinct proteasome interacting proteins regulate proteasome activity in subcellular compartments and in response to cellular signals. Proteasome activators and regulators may thus serve as building blocks to fine-tune proteasome function in the cell according to cellular needs. Inhibitors of the proteasome, e.g. the FDA approved drugs Velcade™, Kyprolis™, Ninlaro™, inactivate the catalytic 20S core and effectively block protein degradation of all proteasome complexes in the cell resulting in inhibition of cell growth and induction of apoptosis. Efficacy of these inhibitors, however, is hampered by their pronounced cytotoxic side-effects as well as by the emerging development of resistance to catalytic proteasome inhibitors. Targeted inhibition of distinct buiding blocks of the proteasome system, i.e. proteasome activators or regulators, represents an alternative strategy to overcome these limitations. In this review, we stress the importance of the diversity of the proteasome complexes constituting an entire proteasome system. Our building block concept provides a rationale for the defined targeting of distinct proteasome super-complexes in disease. We thereby aim to stimulate the development of innovative therapeutic approaches beyond broad catalytic proteasome inhibition.
蛋白酶体是癌症治疗的一个明确的治疗靶点。它作为细胞中主要的蛋白质降解系统，降解细胞生长、存活和功能的关键介质。“蛋白酶体”这个术语包含了一系列不同的复合物，它们具有共同的蛋白酶核心——20S 蛋白酶体，但通过其附着的蛋白酶体激活剂而有所不同。这些蛋白酶体复合物中的每一种都在控制细胞功能方面发挥着特定的作用。此外，不同的蛋白酶体相互作用蛋白在亚细胞区室中调节蛋白酶体活性，并对细胞信号做出反应。因此，蛋白酶体激活剂和调节剂可以作为构建块，根据细胞的需要精细调节细胞内的蛋白酶体功能。蛋白酶体的抑制剂，如已获 FDA 批准的药物 Velcade™、Kyprolis™、Ninlaro™，可使催化性 20S 核心失活，并有效地阻止细胞内所有蛋白酶体复合物的蛋白质降解，从而抑制细胞生长并诱导细胞凋亡。然而，这些抑制剂的疗效受到其明显的细胞毒性副作用以及对催化性蛋白酶体抑制剂的耐药性的出现的限制。靶向抑制蛋白酶体系统的不同构建块，即蛋白酶体激活剂或调节剂，代表了克服这些限制的一种替代策略。在这篇综述中，我们强调了构成完整蛋白酶体系统的蛋白酶体复合物多样性的重要性。我们的构建块概念为针对疾病中不同的蛋白酶体超复合物进行明确靶向提供了理论依据。我们旨在激发超越广泛的催化性蛋白酶体抑制的创新治疗方法的发展。
