Abstract
Developmental down-regulation protein 8 (NEDD8), expressed by neural progenitors, is a ubiquitin-like protein that conjugates to and regulates the biological function of its substrates. The main target of NEDD8 is cullin-RING E3 ligases. Upregulation of the neddylation pathway is closely associated with the progression of various tumors, and MLN4924, which inhibits NEDD8-activating enzyme (NAE), is a promising new antitumor compound for combination therapy. Here, we summarize the latest progress in anticancer strategies targeting the neddylation pathway and their combined applications, providing a theoretical reference for developing antitumor drugs and combination therapies.
Highlights
As a post-translational modification, protein neddylation refers to a process where substrate proteins are tagged with a ubiquitin-like protein NEDD8 and participate in cellular activity by regulating protein function
Different from ubiquitin, as a precursor, NEDD8 is initially synthesized with five additional downstream residues of Gly-76 that must be cracked by a C-terminal hydrolase (Rabut and Peter, 2008), mainly ubiquitin carboxyl-terminal esterase L3 (UCH-L3) (Johnston et al, 1997) and NEDD8 specific-protease cysteine (NEDP1) (Gan-Erdene et al, 2003; Mendoza et al, 2003)
Neddylation modification is catalyzed by an NEDD8-activating enzyme (NAE) (E1), a NEDD8-conjugating enzyme (E2), and a NEDD8 ligase (E3); these factors link a ubiquitin-like molecule, NEDD8, to the lysine residues of the substrate protein
Summary
As a post-translational modification, protein neddylation refers to a process where substrate proteins are tagged with a ubiquitin-like protein NEDD8 and participate in cellular activity by regulating protein function. NEDD8 regulates the activities of substrates and participates in various signaling pathways, including cell proliferation, autophagy and transformation. We summarize and analyse the promising potential of the targeted neddylation pathway as a new therapeutic method and effects of MLN4924/pevonedistat/TAK-924 treatment combined with
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