Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2016-05, Vol.113 (21), p.E2935-E2944
Main Authors: Zhou, Xiaochen, Tan, Mingjia, Nyati, Mukesh K., Zhao, Yongchao, Wang, Gongxian, Sun, Yi
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cancer
Cell Differentiation - drug effects
Clinical trials
Cyclopentanes - pharmacology
Humans
MAP Kinase Signaling System - drug effects
MCF-7 Cells
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, SCID
NEDD8 Protein
PNAS Plus
Proteins
Proto-Oncogene Proteins c-myc - metabolism
Pyrimidines - pharmacology
Rodents
Spheroids, Cellular - metabolism
Stem cells
Stem Cells - metabolism
Tumors
Ubiquitins - antagonists & inhibitors
Ubiquitins - metabolism
Wound Healing - drug effects
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1522367113