title: Targeting protein neddylation with an NEDD8-activating enzyme inhibitor MLN4924 induced apoptosis or senescence in human lymphoma cells.
abstract: Recent studies indicate that post-translational protein neddylation is required for the maintenance of cell viability in several lymphoma cell lines, while inhibition of the neddylation pathway with an NEDD8-activating enzyme (NAE) inhibitor MLN4924 induces apoptosis in lymphoma cells. However, the mechanism by which neddylation inhibition induces apoptosis in lymphoma cells has not been fully elucidated. Moreover, it is unknown whether neddylation inhibition triggers non-apoptotic cell-killing responses, such as cell senescence, in lymphoma cells. Here, we report that MLN4924 specifically inhibited protein neddylation, inactivated cullin-RING E3 ligase (CRL), the best-known neddylation substrate, and induced the accumulation of tumor-suppressive CRL substrates in lymphoma cells. Moreover, MLN4924 potently suppressed the growth of lymphoma cells by inducing G2 cell-cycle arrest, followed by apoptosis or senescence in a cell line-dependent manner. MLN4924-induced apoptosis was mediated by intrinsic apoptotic signaling with substantial up-regulation of pro-apoptotic Bik and Noxa as well as down-regulation of anti-apoptotic XIAP, c-IAP1 and c-IAP2, while senescence induction upon neddylation inhibition seemed dependent on the expression of tumor suppressor p21/p27. Together, these findings expand our understanding on how lymphoma cells respond to neddylation inhibition and support the development of neddylation inhibitors (e.g. MLN4924) for the treatment of lymphoma.
authors.affiliation: a Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology , Shanghai Medical College, Fudan University , Shanghai , PR China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhongguang
authors.initials: Z
authors.lastname: Luo
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Pan
authors.forename: Weige
authors.initials: W
authors.lastname: Wang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D003517:Cyclopentanes / Q000008:administration & dosage*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000075687:NEDD8 Protein; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D014452:Ubiquitins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases; C539933:pevonedistat
keywords: CRL, cullin-RING E3 ligase; GCB-DLBCL, germinal-center B cell-like diffuse large B-cell lymphoma; IAP, inhibitor of apoptosis; MLN4924; NAE, NEDD8-activating enzyme; NHL, non-Hodgkin lymphoma; SA-β-gal, senescence-associated β-galactosidase; apoptosis; lymphoma; neddylation; senescence