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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Overactivated neddylation pathway as a therapeutic target in lung cancer
Lihui Li1, Mingsong Wang1, Guangyang Yu1
1Affiliations of authors: Cancer Institute, Fudan University Shanghai Cancer Center (LL, GY, PC, DW, CL, WY, YW, LJ), Department of Oncology, Shanghai Medical College (LL, GY, PC, DW, CL, WY, YW, LJ), Department of Immunology, School of Basic Medical Sciences (LL, GY, CL, YW, YC, LJ), Clinical Statistics Center, Department of Radiation Oncology, Fudan University Shanghai Cancer Center (JZ, LX, HJ), and Liver Cancer Institute, Zhongshan Hospital (JS, QG), Fudan University, Shanghai, 200032, China; Department of Thoracic Cardiovascular Surgery, Xinhua Hospital of Shanghai Jiaotong University School of Medicine, Shanghai, China (MW, FH, JM); College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China (PC, ZD); Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (HL, PW); College of Pharmacy, Seoul National University, Seoul, Korea (LSJ); College of Pharmacy, Ewha Womans University, Seoul, Korea (LSJ, HWL, JY); AntiCancer Biotech Beijing Co. Ltd., Beijing, China (HQ, MY); Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI (YS); Department of Surgery, University of California, San Diego, CA (RMH); AntiCancer, Inc., San Diego, CA (RMH, MY).
Background:
A number of oncoproteins and tumor suppressors are known to be neddylated, but whether the neddylation pathway is entirely activated in human cancer remains unexplored.
Methods:
NEDD8-activating enzyme (NAE) (E1) and NEDD8-conjugating enzyme (E2) expression and global-protein neddylation were examined by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction analysis. Cell proliferation, clonogenic survival, migration, and motility in vitro, as well as tumor formation and metastasis in vivo, were determined upon neddylation inhibition by MLN4924, an investigational NEDD8-activating enzyme inhibitor. Survival was analyzed with Kaplan-Meier methods and compared by the log-rank test. All statistical tests were two-sided.
Results:
The entire neddylation pathway, including NEDD8-activating enzyme E1, NEDD8-conjugating enzyme E2, and global-protein neddylation, is overactivated in both lung adenocarcinoma and squamous-cell carcinoma. Compared with lung adenocarcinoma patients with low expression, those with high expression had worse overall survival (NEDD8-activating enzyme E1 subunit 1 [NAE1]: hazard ratio [HR] = 2.07, 95% confidence interval [CI] = 0.95 to 4.52, P = .07; ubiquitin-conjugating enzyme E2M (UBC12): HR = 13.26, 95% CI = 1.77 to 99.35, P = .01; global protein neddylation: HR = 3.74, 95% CI = 1.65 to 8.47, P = .002). Moreover, inhibition of neddylation by the NAE inhibitor MLN4924 statistically significantly suppressed proliferation, survival, migration, and motility of lung cancer cells in vitro and tumor formation and metastasis in vivo. At the molecular level, MLN4924 inactivated Cullin-RING E3 ligases, led to accumulation of tumor-suppressive Cullin-RING E3 ligase substrates and induced phorbol-12-myristate-13-acetate-induced protein 1 (NOXA)-dependent apoptosis or cellular senescence.
Conclusions:
Our study highlights the overactivated neddylation pathway in lung cancer development and as a promising therapeutic target.
Insights
The neddylation pathway is overactivated in lung cancer, driving tumor growth and metastasis. Inhibiting this pathway with MLN4924 suppressed cancer progression, highlighting neddylation as a therapeutic target.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Neddylation is a post-translational modification implicated in regulating oncoproteins and tumor suppressors.
- The role and activation status of the neddylation pathway in human cancer, particularly lung cancer, remained largely unexplored.
Purpose of the Study:
- To investigate the activation status of the entire neddylation pathway in lung cancer.
- To evaluate the therapeutic potential of inhibiting the neddylation pathway in lung cancer models.
Main Methods:
- Examined expression of NEDD8-activating enzyme (NAE) E1 and NEDD8-conjugating enzyme (E2), and global protein neddylation using immunohistochemistry, immunoblotting, and RT-PCR.
- Assessed effects of MLN4924, a NAE inhibitor, on lung cancer cell proliferation, survival, migration, and motility in vitro, and tumor formation and metastasis in vivo.
- Analyzed patient survival data based on neddylation pathway component expression.
Main Results:
- The neddylation pathway, including NAE E1, E2, and global neddylation, is significantly overactivated in lung adenocarcinoma and squamous-cell carcinoma.
- High expression of NAE1, UBC12, and global neddylation correlated with worse overall survival in lung adenocarcinoma patients.
- MLN4924 treatment significantly inhibited lung cancer cell proliferation, survival, migration, and motility in vitro, and suppressed tumor formation and metastasis in vivo.
- MLN4924 induced apoptosis and cellular senescence by inactivating Cullin-RING E3 ligases and accumulating their substrates, including NOXA.
Conclusions:
- The neddylation pathway is a key driver in lung cancer development and progression.
- Targeting the neddylation pathway with inhibitors like MLN4924 represents a promising therapeutic strategy for lung cancer.
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