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Targeting neddylation inhibits intravascular survival and extravasation of cancer cells to prevent lung-cancer metastasis.
Cell Biology and Toxicology ( IF 6.1 ) Pub Date : 2019-05-28 , DOI: 10.1007/s10565-019-09472-w
Yanyu Jiang 1, 2, 3 , Yupei Liang 1, 2, 3 , Lihui Li 2 , Lisha Zhou 2, 4 , Wei Cheng 2 , Xi Yang 2 , Xuguang Yang 2 , Hui Qi 5, 6 , Jinha Yu 7 , Lak Shin Jeong 7 , Robert M Hoffman 5 , Peiyong Zheng 8 , Lijun Jia 1, 2
Affiliation  

Metastasis is the leading cause of tumor-related death from lung cancer. However, limited success has been achieved in the treatment of lung cancer metastasis due to the lack of understanding of the mechanisms that underlie the metastatic process. In this study, Lewis lung carcinoma (LLC) cells which expressed green fluorescent protein in the nucleus and red fluorescent protein in the cytoplasm were used to record metastatic process in real-time via a whole-mouse imaging system. Using this system, we show the neddylation inhibitor MLN4924 inhibits multiple steps of the metastatic process, including intravascular survival, extravasation, and formation of metastatic colonies, thus finally suppressing tumor metastasis. Mechanistically, MLN4924 efficiently inhibits the expression of MMP2, MMP9, and vimentin and disrupts the actin cytoskeleton at an early stage to impair invasive potential and subsequently causes a DNA damage response, cell cycle arrest, and apoptosis upon long exposure to MLN4924. Furthermore, MMP2 and MMP9 are overexpressed in patient lung adenocarcinoma, which conferred a worse overall survival. Together, targeting the neddylation pathway via MLN4924 suppresses multiple steps of the metastatic process, highlighting the potential therapeutic value of MLN4924 for the treatment of metastatic lung cancer.

中文翻译:

靶向腺苷酸化可抑制血管内存活和癌细胞外渗,从而防止肺癌转移。

转移是肺癌与肿瘤相关的死亡的主要原因。但是,由于对转移过程基础的机制缺乏了解,因此在治疗肺癌转移中取得的成功有限。在这项研究中,使用在细胞核中表达绿色荧光蛋白并在细胞质中表达红色荧光蛋白的Lewis肺癌(LLC)细胞通过全小鼠成像系统实时记录转移过程。使用该系统,我们显示出降糖肽抑制剂MLN4924可抑制转移过程的多个步骤,包括血管内存活,外渗和转移集落的形成,从而最终抑制肿瘤转移。从机制上讲,MLN4924有效抑制MMP2,MMP9,波形蛋白和波形蛋白,并在早期破坏肌动蛋白的细胞骨架以削弱侵袭潜能,并在长时间暴露于MLN4924后引起DNA损伤反应,细胞周期停滞和凋亡。此外,MMP2MMP9在患者肺腺癌中过表达,这使总生存期变差。总之,通过MLN4924靶向neddylation途径可抑制转移过程的多个步骤,从而凸显MLN4924在治疗转移性肺癌中的潜在治疗价值。
更新日期:2019-05-28
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