Targeting Protein Neddylation for Cancer Therapy
Targeting Protein Neddylation for Cancer Therapy
复制标题
靶向蛋白质 Neddylation 用于癌症治疗
DOI：
10.1007/978-981-15-1025-0_18
复制
发表时间：
2020-01-01
期刊：
影响因子：
--
通讯作者：
Jia, Lijun
中科院分区：
文献类型：
--
作者：
Zhou, Lisha;Jia, Lijun
Neddylation是一种翻译后修饰，将泛素样蛋白NEDD 8与底物蛋白结合。neddylation的最佳特征底物是cullin-RING E3泛素连接酶复合物（CRL）的cullin亚基。CRLs作为E3泛素连接酶中最大的家族，通过促进多种关键调控蛋白的泛素化及随后的降解，控制包括肿瘤发生在内的许多重要生物学过程。蛋白质neddylation过程在多种类型的人类癌症中被过度激活，提供了作为有吸引力的抗癌治疗策略的合理依据，NEDD 8激活酶（NAE）抑制剂MLN 4924（也称为pevonedistat）的开发证明了这一点。最近，越来越多的证据强烈表明MLN 4924的neddylation抑制作用主要通过触发细胞凋亡、衰老和自噬以及以环境依赖性方式引起血管生成抑制、炎症反应和化疗/放射增敏来发挥抗癌作用。本文简要综述了这一领域的最新进展，重点介绍了neddylation修饰作为一个有前途的抗癌靶点的临床前研究。
Neddylation is a posttranslational modification that conjugates a ubiquitin-like protein NEDD8 to substrate proteins. The bestcharacterized substrates of neddylation are the cullin subunits of cullin-RING E3 ubiquitin ligase complexes (CRLs). CRLs as the largest family of E3 ubiquitin ligases control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins. The process of protein neddylation is overactivated in multiple types of human cancers, providing a sound rationale as an attractive anticancer therapeutic strategy, evidenced by the development of the NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Recently, increasing evidence strongly indicates that neddylation inhibition by MLN4924 exerts anticancer effects mainly by triggering cell apoptosis, senescence, and autophagy and causing angiogenesis suppression, inflammatory responses, and chemo-/ radiosensitization in a context-dependent manner. Here, we briefly summarize the latest progresses in this field, focusing on the preclinical studies to validate neddylation modification as a promising anticancer target.