Effective targeting of the ubiquitin-like modifier NEDD8 for lung adenocarcinoma treatment.

Cell biology and toxicology 2020 Aug

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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 G2 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.

Citation

Yanyu Jiang, Wei Cheng, Lihui Li, Lisha Zhou, Yupei Liang, Wenjuan Zhang, Wenlian Chen, Shiwen Wang, Hu Zhao, Guoan Chen, Wenjun Zhou, Guang Ji, Yanmei Zhang, Robert M Hoffman, Mingsong Wang, Lijun Jia. Effective targeting of the ubiquitin-like modifier NEDD8 for lung adenocarcinoma treatment. Cell biology and toxicology. 2020 Aug;36(4):349-364