TY - JOUR
T1 - Overactivated neddylation pathway as a therapeutic target in lung cancer
AU - Li, Lihui
AU - Wang, Mingsong
AU - Yu, Guangyang
AU - Chen, Ping
AU - Li, Hui
AU - Wei, Dongping
AU - Zhu, Ji
AU - Xie, Li
AU - Jia, Huixun
AU - Shi, Jieyi
AU - Li, Chunjie
AU - Yao, Wantong
AU - Wang, Yanchun
AU - Gao, Qiang
AU - Jeong, Lak Shin
AU - Lee, Hyuk Woo
AU - Yu, Jinha
AU - Hu, Fengqing
AU - Mei, Ju
AU - Wang, Ping
AU - Chu, Yiwei
AU - Qi, Hui
AU - Yang, Meng
AU - Dong, Ziming
AU - Sun, Yi
AU - Hoffman, Robert M.
AU - Jia, Lijun
PY - 2014/6/11
Y1 - 2014/6/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84905164592&partnerID=8YFLogxK
U2 - 10.1093/jnci/dju083
DO - 10.1093/jnci/dju083
M3 - Article
C2 - 24853380
AN - SCOPUS:84905164592
SN - 0027-8874
VL - 106
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 6
ER -
