title: Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells.
abstract: MLN4924 is a recently discovered small molecule inhibitor of NEDD8-Activating Enzyme (NAE). Because cullin RING ligase (CRL), the largest family of E3 ubiquitin ligase, requires cullin neddylation for its activity, MLN4924, therefore, acts as an indirect inhibitor of CRL by blocking cullin neddylation. Given that CRLs components are up-regulated, whereas neddylation modification is over-activated in a number of human cancers, MLN4924 was found to be effective in growth suppression of cancer cells. Whether MLN4924 is effective against gastric cancer cells, however, remains elusive. Here we showed that in gastric cancer cells, MLN4924 rapidly inhibited cullin 1 neddylation and remarkably suppressed growth and survival as well as migration in a dose-and time-dependent manner. Mechanistic studies in combination with siRNA knockdown-based rescue experiments revealed that MLN4924 induced the accumulation of a number of CRL substrates, including CDT1/ORC1, p21/p27, and PHLPP1 to trigger DNA damage response and induce growth arrest at the G2/M phase, to induce senescence, as well as autophagy, respectively. MLN4924 also significantly suppressed migration by transcriptionally activating E-cadherin and repressing MMP-9. Taken together, our study suggest that neddylation modification and CRL E3 ligase are attractive gastric cancer targets, and MLN4924 might be further developed as a potent therapeutic agent for the treatment of gastric cancer.
authors.affiliation: Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China.|Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310020, China.
authors.forename: Huiyin
authors.initials: H
authors.lastname: Lan
authors.affiliation: Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China.
authors.forename: Zaiming
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310020, China.
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Jin
authors.affiliation: Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.|Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI 48109, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
mesh_terms: D001343:Autophagy / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects; D044842:Cullin Proteins / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D000075687:NEDD8 Protein; D009687:Nuclear Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014452:Ubiquitins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C467199:CDT1 protein, human; D015820:Cadherins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D009687:Nuclear Proteins; D011743:Pyrimidines; C479529:RBX1 protein, human; D034741:RNA, Small Interfering; D014452:Ubiquitins; C118307:RNF7 protein, human; D044767:Ubiquitin-Protein Ligases; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases; D020780:Matrix Metalloproteinase 9; C539933:pevonedistat