Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target
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Qiang Gao1,*, Guang-Yang Yu2,*, Jie-Yi Shi1,*, Li-Hui Li2,*, Wen-Juan Zhang2, Zhi-Chao Wang1, Liu-Xiao Yang1, Meng Duan1, Hu Zhao3, Xiao-Ying Wang1, Jian Zhou1,4, Shuang-Jian Qiu1, Lak Shin Jeong5, Li-Jun Jia2 and Jia Fan1,4
1 Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, P. R. China
2 Cancer Institute, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P. R. China
3 Department of Laboratory Medicine, Laboratory of Molecular Biology of Huadong Hospital, Fudan University, Shanghai, P. R. China
4 Institute of Biomedical Sciences, Fudan University, Shanghai, P. R. China
5 College of Pharmacy, Seoul National University, Seoul, Korea
* These authors contributed equally to this work
Jia Fan, email:
Li-Jun Jia, email:
Lak Shin Jeong, email:
Keywords: Intrahepatic cholangiocarcinoma; Neddylation; NEDD8; MLN4924; Cullin-Ring ligase
Received: June 06, 2014 Accepted: August 03, 2014 Published: August 04, 2014
Therapeutic intervention in neddylation pathway is an emerging area for cancer treatment. Herein, we evaluated the clinical relevance and therapeutic potential of targeting this pathway in intrahepatic cholangiocarcinoma (ICC). Immunohistochemistry of neddylation pathway components in a cohort of 322 cases showed that E1 (NAE1 and UBA3) and E2 (UBC12) enzymes, as well as global NEDD8 conjugation, were upregulated in over 2/3 of human ICC. Notably, NAE1 was identified as an independent prognosticator for postoperative recurrence (P=0.009) and a combination of NEDD8 and NAE1 provided a better power for predicting patient clinical outcomes. In vitro treatment with MLN4924, a small-molecule NEDD8-activating enzyme inhibitor, led to a dose-dependent decrease of viability in both established and primary cholangiocarcinoma cell lines. Additionally, MLN4924 exhibited at least additive effect when combined with cisplatin. By blocking cullins neddylation, MLN4924 inactivated Cullin-Ring ligase (CRL) and caused the accumulation of CRL substrates that triggered cell cycle arrest, senescence or apoptosis. Meanwhile, MLN4924 was well-tolerated and significantly inhibited tumor growth in xenograft model of cholangiocarcinoma. Taken together, our findings indicated that upregulated neddylation pathway was involved in ICC progression and interference in this pathway could be a promising target for ICC therapy.
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