Division of Hematology-Oncology, Department of Internal Medicine, The Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267, USA.
Semin Hematol. 2012 Jul;49(3):277-83. doi: 10.1053/j.seminhematol.2012.04.002.
The ubiquitin+proteasome system (UPS) is a highly complex network that maintains protein homeostasis and cell viability through the selective turnover of targeted substrates. The proteasome serves as the catalytic core of the UPS to recognize and execute the coordinated and efficient removal of ubiquitinated proteins. Pharmacologic inhibitors that exploit the pivotal role of the proteasome in cellular metabolism promote tumor cytotoxicity and have yielded durable clinical responses that dramatically improve patient survival. Success of the proteasome inhibitor (PI) bortezomib in the treatment of the hematologic malignancy multiple myeloma (MM) has emerged as the standard-of-care and catapulted the UPS into a position of prominence as a model system in cancer biology and drug development. However, expansion of PIs in the treatment of the more complex solid tumors has been less successful. While clinical evaluation of second-generation PIs progresses, other potential sites of therapeutic intervention within the UPS continue to emerge, such as the non-proteolytic activities associated with the proteasome and the rapidly expanding number of Ub-binding proteins. Molecular-genetic approaches to further unravel the complexity of the UPS will advance its utilization as a platform for the development of novel, mechanism-based anticancer strategies.
泛素-蛋白酶体系统（UPS）是一个高度复杂的网络，通过靶向底物的选择性降解来维持蛋白质平衡和细胞活力。蛋白酶体作为 UPS 的催化核心，可识别并执行协调有效的泛素化蛋白的去除。利用蛋白酶体在细胞代谢中关键作用的药理学抑制剂可促进肿瘤细胞毒性，并产生持久的临床反应，显著提高患者的生存率。蛋白酶体抑制剂（PI）硼替佐米在治疗血液恶性肿瘤多发性骨髓瘤（MM）中的成功应用已成为标准治疗方法，并将 UPS 推到了癌症生物学和药物开发的模型系统的突出地位。然而，PI 在更复杂的实体瘤治疗中的应用并不成功。虽然第二代 PI 的临床评估正在进行，但 UPS 内其他潜在的治疗干预靶点仍在不断涌现，例如与蛋白酶体相关的非蛋白水解活性以及数量迅速增加的 Ub 结合蛋白。进一步揭示 UPS 复杂性的分子遗传学方法将促进其作为开发新型基于机制的抗癌策略的平台的应用。
