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

Jiang，Yanyu1; Cheng，Wei1; Li，Lihui1; Zhou，Lisha1,2; Liang，Yupei1; Zhang，Wenjuan1,3; Chen，Wenlian1; Wang，Shiwen4; Zhao，Hu4; Chen，Guoan5; Zhou，Wenjun6; Ji，Guang6; Zhang，Yanmei4; Hoffman，Robert M.7,8; Wang，Mingsong9; Jia，Lijun1

2020

10.1007/s10565-019-09503-6

CELL BIOLOGY AND TOXICOLOGY   影响因子和分区

0742-2091

1573-6822

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 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.

apoptosis cullin-RING ligases NEDD8 neddylation senescence

SCI

英语

其他

Innovation Program of Shanghai Municipal Education Commission[2019-01-07-00-10-E00056] ; National Natural Science Foundation of China[81625018, 81820108022, 81772459, 81572340, 81602072, 81772470 and 81702244] ; National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development[2017ZX09304001] ; the Chinese Minister of Science and Technology grant[2016YFA0501800] ; Shuguang Program supported by Shanghai Education Development Foundation[14SG07] ; Program of Shanghai Academic/Technology Research Leader[18XD1403800]

Cell Biology ; Toxicology

Cell Biology ; Toxicology

WOS:000548689000005

SPRINGER

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85077558947

Scopus

1.Cancer Institute,Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai,200032,China
2.Department of Biochemistry,Medical College,Taizhou University,Zhejiang,Taizhou,317000,China
3.Cancer Institute,Fudan University Shanghai Cancer Center; Department of Oncology,Shanghai Medical College,Fudan University,Shanghai,200032,China
4.Department of Laboratory Medicine,Huadong Hospital Fudan University,Shanghai,China
5.School of Medicine,Southern University of Science and Technology,Shenzhen,China
6.Institute of Digestive Diseases,Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai,China
7.Department of Surgery,University of California,San Diego,United States
8.Anticancer Inc,San Diego,United States
9.Department of Cardiothoracic Surgery,Xinhua Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai,China

Jiang，Yanyu,Cheng，Wei,Li，Lihui,et al. Effective targeting of the ubiquitin-like modifier NEDD8 for lung adenocarcinoma treatment[J]. CELL BIOLOGY AND TOXICOLOGY,2020,36(4):349-364.

Jiang，Yanyu.,Cheng，Wei.,Li，Lihui.,Zhou，Lisha.,Liang，Yupei.,...&Jia，Lijun.(2020).Effective targeting of the ubiquitin-like modifier NEDD8 for lung adenocarcinoma treatment.CELL BIOLOGY AND TOXICOLOGY,36(4),349-364.

Jiang，Yanyu,et al."Effective targeting of the ubiquitin-like modifier NEDD8 for lung adenocarcinoma treatment".CELL BIOLOGY AND TOXICOLOGY 36.4(2020):349-364.