Effective targeting of the ubiquitin-like modifier NEDD8 for lung adenocarcinoma treatment
Effective targeting of the ubiquitin-like modifier NEDD8 for lung adenocarcinoma treatment
复制标题
泛素样修饰剂 NEDD8 有效靶向治疗肺腺癌
DOI：
10.1007/s10565-019-09503-6
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发表时间：
2020-08-01
影响因子：
6.1
通讯作者：
Jia, Lijun
中科院分区：
文献类型：
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作者：
Jiang, Yanyu;Cheng, Wei;Jia, Lijun
蛋白质neddylation是神经前体细胞表达的发育下调8（NEDD8）与底物结合的过程，在肺癌发生中发挥肿瘤促进作用。我们之前的研究表明MLN4924是NEDD8激活酶（E1）的抑制剂，可显着抑制多种癌细胞的生长。然而，MLN4924 可能会因突变而产生耐药性。因此，进一步了解 NEDD8 在肺癌中的作用非常重要。在本研究中，我们证明 NEDD8 在肺癌中过度激活，导致患者总生存期较差。此外，我们报告在肺腺癌细胞中，NEDD8 缺失在体外和体内均显着抑制肺癌细胞的生长和进展。机制研究表明，NEDD8 缺失通过阻止其降解诱导一组肿瘤抑制性 cullin-RING 泛素连接酶底物（例如 p21、p27 和 Wee1）的积累，触发细胞周期停滞在 G(2) 期，从而以细胞系依赖性方式诱导细胞凋亡或衰老。本研究证明了NEDD8在调节肺癌细胞恶性表型中的作用，并进一步验证了NEDD8作为肺癌的潜在治疗靶点。
Protein neddylation, a process of conjugating neural precursor cell expressed, developmentally downregulated 8 (NEDD8) to substrates, plays a tumor-promoting role in lung carcinogenesis. Our previous study showed MLN4924, an inhibitor of NEDD8 activating enzyme (E1), significantly inhibits the growth of multiple cancer cells. However, resistance can develop to MLN4924 by mutation. Therefore, it is important to further understand how NEDD8 acts in lung cancer. In the present study, we demonstrated NEDD8 is overactivated in lung cancers and confers a worse patient overall survival. Furthermore, we report that in lung adenocarcinoma cells, NEDD8 depletion significantly suppressed lung cancer cell growth and progression both in vitro and in vivo. Mechanistic studies revealed that NEDD8 depletion induced the accumulation of a panel of tumor-suppressive cullin-RING ubiquitin ligase substrates (e.g., p21, p27, and Wee1) via blocking their degradation, triggering cell cycle arrest at G(2)phase, thus inducing apoptosis or senescence in a cell-line-dependent manner. The present study demonstrates the role of NEDD8 in regulating the malignant phenotypes of lung cancer cells and further validates NEDD8 as a potential therapeutic target in lung cancer.