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

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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. Significance MLN4924, a potent small-molecule inhibitor of NEDD8-activating enzyme, blocks cullin-RING ligase activity through inhibiting cullin neddylation. MLN4924 is widely used in both preclinical and clinical settings for an anticancer application. We report here an unexpected finding: MLN4924 at nanomolar concentration stimulates stem cell proliferation, self-renewal, and differentiation in both tumor and normal stem cell models and promotes skin wound healing in a mouse model and cell migration in vitro. Mechanistic studies revealed that MLN4924 causes c-MYC accumulation and promotes EGFR (epidermal growth factor receptor) dimerization to activate the EGFR signaling pathway. Our study raises a concern in anticancer application of MLN4924, but at the same time provides an opportunity for future development of MLN4924 as an agent for stem cell therapy and tissue regeneration.
Funding Information
  • Foundation for the National Institutes of Health (CA118762)
  • Foundation for the National Institutes of Health (CA156744)
  • Foundation for the National Institutes of Health (CA171277)
  • National Natural Science Foundation of China (81460389)
  • National Natural Science Foundation of China (31470753)
  • National Natural Science Foundation of China (81572718)

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