MLN4924抑制NEDD化，并诱导人骨肉瘤细胞发生细胞周期阻滞、衰老和凋亡。
MLN4924 suppresses neddylation and induces cell cycle arrest, senescence, and apoptosis in human osteosarcoma.
作者信息
Zhang Yi, Shi Cheng-Cheng, Zhang Hua-Peng, Li Gong-Quan, Li Shan-Shan
机构信息
Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
The Hormel Institute, University of Minnesota, Austin, MN, USA.
出版信息
Oncotarget. 2016 Jul 19;7(29):45263-45274. doi: 10.18632/oncotarget.9481.
Neddylation is a post-translational protein modification process associated with carcinogenesis and cancer development. MLN4924, a pharmaceutical neddylation inhibitor, induces potent anti-cancer effects in multiple types of cancers. In this study, we investigated the effects of MLN4924 on human osteosarcoma (OS). Levels of both NEDD8 activating enzyme E1 (NAE1) and ubiquitin-conjugating enzyme E2M (Ube2M), two critical components of the neddylation pathway, were much higher in OS tissues and cells than in normal osseous tissues and cells. MLN4924 treatment led to DNA damage, reduced cell viability, senescence and apoptosis in OS cells. Moreover, MLN4924 inhibited OS xenograft tumor growth in mice. Mechanistically, MLN4924 blocked the neddylation of cullins and induced accumulation of several tumor-suppressive substrates of Cullin-RING E3 ubiquitin ligases (CRLs), including CDT1, Wee1, p21, p27, Noxa, and p16. These results suggest clinical studies investigating the utility of MLN4924 for the treatment of OS are warranted.
Neddylation是一种与癌症发生和发展相关的翻译后蛋白质修饰过程。MLN4924是一种药物性Neddylation抑制剂，在多种癌症类型中诱导强大的抗癌作用。在本研究中，我们研究了MLN4924对人骨肉瘤（OS）的影响。Neddylation途径的两个关键成分NEDD8激活酶E1（NAE1）和泛素结合酶E2M（Ube2M）在OS组织和细胞中的水平远高于正常骨组织和细胞。MLN4924处理导致OS细胞中的DNA损伤、细胞活力降低、衰老和凋亡。此外，MLN4924抑制了小鼠OS异种移植肿瘤的生长。从机制上讲，MLN4924阻断了cullins的Neddylation，并诱导了Cullin-RING E3泛素连接酶（CRLs）的几种肿瘤抑制底物的积累，包括CDT1、Wee1、p21、p27、Noxa和p16。这些结果表明，有必要进行临床研究以调查MLN4924治疗OS的效用。
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