title: Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo.
abstract: MLN4924, also known as pevonedistat, is the first-in-class inhibitor of NEDD8-activating enzyme, which blocks the entire neddylation modification of proteins. Previous preclinical studies and current clinical trials have been exclusively focused on its anticancer property. Unexpectedly, we show here, to our knowledge for the first time, that MLN4924, when applied at nanomolar concentrations, significantly stimulates in vitro tumor sphere formation and in vivo tumorigenesis and differentiation of human cancer cells and mouse embryonic stem cells. These stimulatory effects are attributable to (i) c-MYC accumulation via blocking its degradation and (ii) continued activation of EGFR (epidermal growth factor receptor) and its downstream pathways, including PI3K/AKT/mammalian target of rapamycin and RAS/RAF/MEK/ERK, via inducing EGFR dimerization. Finally, MLN4924 accelerates EGF-mediated skin wound healing in mouse and stimulates cell migration in an in vitro culture setting. Taking these data together, our study reveals that neddylation modification could regulate stem cell proliferation and differentiation and that a low dose of MLN4924 might have a therapeutic value for stem cell therapy and tissue regeneration.
authors.affiliation: Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Mingjia
authors.initials: M
authors.lastname: Tan
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Nyati
authors.affiliation: Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China;
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; sunyi@umich.edu wanggx-mr@126.com.
authors.forename: Gongxian
authors.initials: G
authors.lastname: Wang
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310058, China sunyi@umich.edu wanggx-mr@126.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D003517:Cyclopentanes / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D000075687:NEDD8 Protein; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D003517:Cyclopentanes; C489427:MYC protein, human; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D014452:Ubiquitins; C539933:pevonedistat
keywords: EGFR; MLN4924; neddylation; stem cell; wound healing