title: Suppression of tumor angiogenesis by targeting the protein neddylation pathway.
abstract: Inhibition of protein neddylation, particularly cullin neddylation, has emerged as a promising anticancer strategy, as evidenced by the antitumor activity in preclinical studies of the Nedd8-activating enzyme (NAE) inhibitor MLN4924. This small molecule can block the protein neddylation pathway and is now in clinical trials. We and others have previously shown that the antitumor activity of MLN4924 is mediated by its ability to induce apoptosis, autophagy and senescence in a cell context-dependent manner. However, whether MLN4924 has any effect on tumor angiogenesis remains unexplored. Here we report that MLN4924 inhibits angiogenesis in various in vitro and in vivo models, leading to the suppression of tumor growth and metastasis in highly malignant pancreatic cancer, indicating that blockage of angiogenesis is yet another mechanism contributing to its antitumor activity. At the molecular level, MLN4924 inhibits Cullin-RING E3 ligases (CRLs) by cullin deneddylation, causing accumulation of RhoA at an early stage to impair angiogenic activity of vascular endothelial cells and subsequently DNA damage response, cell cycle arrest and apoptosis due to accumulation of other tumor-suppressive substrates of CRLs. Furthermore, we showed that inactivation of CRLs, via small interfering RNA (siRNA) silencing of its essential subunit ROC1/RBX1, recapitulates the antiangiogenic effect of MLN4924. Taken together, our study demonstrates a previously unrecognized role of neddylation in the regulation of tumor angiogenesis using both pharmaceutical and genetic approaches, and provides proof of concept evidence for future development of neddylation inhibitors (such as MLN4924) as a novel class of antiangiogenic agents.
authors: 1] Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [2] Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China [3] Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
authors: W-T
authors: WT
authors: Yao
authors: 1] Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [2] Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: J-F
authors: JF
authors: Wu
authors: 1] Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [2] Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: G-Y
authors: GY
authors: Yu
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors: R
authors: R
authors: Wang
authors: State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, Nanjing University, Nanjing, China.
authors: K
authors: K
authors: Wang
authors: Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors: L-H
authors: LH
authors: Li
authors: Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors: P
authors: P
authors: Chen
authors: 1] Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [2] Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: Y-N
authors: YN
authors: Jiang
authors: Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
authors: H
authors: H
authors: Cheng
authors: College of Pharmacy, Seoul National University, Seoul, Korea.
authors: H W
authors: HW
authors: Lee
authors: College of Pharmacy, Seoul National University, Seoul, Korea.
authors: J
authors: J
authors: Yu
authors: AntiCancer Biotech Beijing Co. Ltd, Beijing, China.
authors: H
authors: H
authors: Qi
authors: Department of Pancreas and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
authors: X-J
authors: XJ
authors: Yu
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors: P
authors: P
authors: Wang
authors: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: Y-W
authors: YW
authors: Chu
authors: AntiCancer Biotech Beijing Co. Ltd, Beijing, China.
authors: M
authors: M
authors: Yang
authors: State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, Nanjing University, Nanjing, China.
authors: Z-C
authors: ZC
authors: Hua
authors: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: H-Q
authors: HQ
authors: Ying
authors: 1] Department of Surgery, University of California, San Diego, CA, USA [2] AntiCancer, Inc., San Diego, CA, USA.
authors: R M
authors: RM
authors: Hoffman
authors: College of Pharmacy, Seoul National University, Seoul, Korea.
authors: L S
authors: LS
authors: Jeong
authors: 1] Cancer Institute, Fudan University Shanghai Cancer Center; Collaborative Innovation Center of Cancer Medicine; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [2] Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors: L-J
authors: LJ
authors: Jia
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply*; D044842:Cullin Proteins / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D000075687:NEDD8 Protein; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D002352:Carrier Proteins; D044842:Cullin Proteins; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; C479529:RBX1 protein, human; D014452:Ubiquitins; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat