Synergistic inhibition of autophagy and neddylation pathways as a novel therapeutic approach for targeting liver cancer
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Ping Chen1,2,3,4, Tao Hu2,4, Yupei Liang1, Yanan Jiang1,3, Yongfu Pan1,3, Chunjie Li1,3, Ping Zhang1, Dongping Wei1, Pei Li2,4, Lak Shin Jeong5, Yiwei Chu3, Hui Qi6,7, Meng Yang6,7, Robert M. Hoffman7,8, Ziming Dong2,4, Lijun Jia1
1Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
2College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
3Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, China
4Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, China
5College of Pharmacy, Seoul National University, Seoul, Korea
6AntiCancer Biotech Beijing Co. Ltd., Beijing, China
7Anticancer, Inc., San Diego, CA, USA
8Department of Surgery, University of California, San Diego, CA, USA
Lijun Jia, e-mail: [email protected]
Keywords: Neddylation, Autophagy, Apoptosis, MLN4924, Chloroquine
Received: December 23, 2014 Accepted: February 05, 2015 Published: March 13, 2015
Liver cancer is the second-most frequent cause of cancer death in the world and is highly treatment resistant. We reported previously that inhibition of neddylation pathway with specific NAE inhibitor MLN4924, suppressed the malignant phenotypes of liver cancer. However, during the process, MLN4924 induces pro-survival autophagy as a mechanism of drug resistance. Here, we report that blockage of autophagy with clinically-available autophagy inhibitors (e.g. chloroquine) significantly enhanced the efficacy of MLN4924 on liver cancer cells by triggering apoptosis. Mechanistically, chloroquine enhanced MLN4924-induced up-regulation of pro-apoptotic proteins (e.g. NOXA) and down-regulation of anti-apoptotic proteins. Importantly, the down-regulation of NOXA expression via siRNA silencing substantially attenuated apoptosis of liver cancer cells. Further mechanistic studies revealed that blockage of autophagy augmented MLN4924-induced DNA damage and reactive oxygen species (ROS) generation. The elimination of DNA damage or blockage of ROS production significantly reduced the expression of NOXA, and thereby attenuated apoptosis and reduced growth inhibition of liver cancer cells. Moreover, blockage of autophagy enhanced the efficacy of MLN4924 in an orthotopic model of human liver cancer, with induction of NOXA and apoptosis in tumor tissues. These findings provide important preclinical evidence for clinical investigation of synergistic inhibition of neddylation and autophagy in liver cancer.
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