Targeting the Ubiquitin plus Proteasome System in Solid Tumors
Targeting the Ubiquitin plus Proteasome System in Solid Tumors
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DOI：
10.1053/j.seminhematol.2012.04.002
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发表时间：
2012-07-01
影响因子：
3.6
通讯作者：
Woodle, E. Steve
中科院分区：
文献类型：
--
作者：
Driscoll, James J.;Woodle, E. Steve
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周转来维持蛋白质稳态和细胞活力。蛋白酶体作为UPS的催化核心，识别和执行协调和有效的去除泛素化蛋白。利用蛋白酶体在细胞代谢中的关键作用的药理学抑制剂促进肿瘤细胞毒性，并产生了持久的临床反应，大大提高了患者的生存率。蛋白酶体抑制剂（PI）硼替佐米在血液恶性肿瘤多发性骨髓瘤（MM）治疗中的成功已经成为标准治疗，并使UPS成为癌症生物学和药物开发中的模型系统。然而，在更复杂的实体瘤的治疗中Pis的扩展不太成功。虽然第二代PI的临床评价正在进行中，但UPS内其他潜在的治疗干预位点继续出现，例如与蛋白酶体相关的非蛋白水解活性和快速增加的Ub结合蛋白数量。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的基于机制的抗癌策略的平台的利用。Semin Hematol 49：277-283. (C)2012 Elsevier Inc. All rights reserved.
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. Semin Hematol 49:277-283. (C) 2012 Elsevier Inc. All rights reserved.