Targeting neddylation as a novel approach to lung cancer treatment (Review)

Abstract

As a protein that resembles ubiquitin, neural precursor cell expressed developmentally downregulated 8 (NEDD8) takes part in neddylation, which modifies substrates in a manner similar to ubiquitination and alters the activity of target proteins. Neddylation may affect the activity of multiple signaling pathways, have a regulatory role in tumor formation, progression and metastasis, and influence the prognosis of cancer treatment. The present review summarizes the regulatory roles of NEDD8 in the MDM2‑p53, NF‑κB, PI3K/AKT/mTOR, hypoxia‑inducible factor, Hippo and receptor tyrosine kinase signaling pathways, as well as in the development and progression of lung cancer.

Keywords: MLN4924; NEDD8; lung cancer; neddylation; signaling pathway; treatment.

Figure 1

The neddylation modification process and the deneddylation modification process. First, enzymes such as NEDP1 are involved in the hydrolysis of NEDD8 precursors. NAE is then involved in the activation of NEDD8, thus binding to enzyme E2, at which time NAE leaves. Ligase E3 binds to E2, which carries the substrate and transfers NEDD8 to the substrate. CSN or NEDP1 participates in the depolymerization of NEDD8 from the substrate, known as deneddylation. NEDD8, neural precursor cell expressed developmentally downregulated 8; NAE, NEDD8-activating enzyme; NEDP1, NEDD8 protease 1; CSN, constitutive photomorphogenesis signalosome; USP21, ubiquitin-specific peptidase 21; UCH-LC3, ubiquitin C-terminal hydrolase-LC3.

Figure 2

NEDD8 regulates the ubiquitin-proteasome degradation pathways related to CRL and MDM2, and it realizes the regulation of proteins by promoting the NF-κB, PI3K/AKT/mTOR, Hippo-YAP and receptor tyrosine kinase signaling pathways. NEDD8 also inhibits MDM2-p53, HIF and other signaling pathways, which in turn affects DNA damage repair, the cell cycle and tumor development. HIF, hypoxia-inducible factor; CRL, cullin-ring ligase; EMT, epithelial to mesenchymal transition; NEDD8, neural precursor cell expressed developmentally downregulated 8; NAE, NEDD8-activating enzyme; NEDP1, NEDD8 protease 1; CSN, constitutive photomorphogenesis signalosome; PTEN, phosphatase and tensin homolog; VHL, von Hippel-Lindau; Mst1/2, mammalian sterile 20-like kinase 1/2; YAP, Yes-associated protein; MDM2, murine double minute 2; PI3K, phosphatidylinositol-3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; LATS1/2, large tumor suppressor homolog 1/2; EGFR, epidermal growth factor receptor; TGFβRII, TGF-β type II receptor.

Figure 3

Several signaling pathways are closely related to NEDD8. L11 is modified by NEDD8 and remains in the nucleolus; in contrast, unmodified L11 enters the nucleoplasm to bind to MDM2, thereby promoting the transcriptional activation of p53. IκB, the inhibitor of NF-κB, is recognized by NEDD8-modified SCF after phosphorylation, thereby degrading it and activating the NF-κB signaling pathway. In the PI3K/AKT/mTOR signaling pathway, PTEN is modified by NEDD8 and moves into the nucleus, promoting the phosphorylation of PIP2 and activating downstream pathways. NEDD8, neural precursor cell expressed developmentally downregulated 8; PTEN, phosphatase and tensin homolog; CSN, constitutive photomorphogenesis signalosome; MDM2, murine double minute 2; SCF, Skp1-CUL1-F-box protein; PI3K, phosphatidylinositol-3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; PDK1, phosphoinositide-dependent kinase 1; RBX, ring-box; NEDP1, NEDD8 protease 1.

Figure 4

Several signaling pathways are closely related to NEDD8. In the HIF signaling pathway, VHL binds to NEDD8-modified CUL2, thereby ubiquitinating HIF-1α; NEDD8-modified VHL inhibits this process. The Hippo-YAP pathway requires NEDD8 for a series of phosphorylation reactions. For instance, NEDD8-modified CUL7 promotes Mst1 degradation and NEDD8-modified CUL4 promotes LATS1/2 degradation. In the RTK signaling pathway, TGFβRII and EGFR are also modified by NEDD8 to remain stable. HIF, hypoxia-inducible factor; NEDD8, neural precursor cell expressed developmentally downregulated 8; Mst1/2, mammalian sterile 20-like kinase 1/2; YAP, Yes-associated protein; RTK, receptor tyrosine kinase; TGFβRII, TGF-β type II receptor; EGFR, epidermal growth factor receptor; TEAD, transcriptional enhanced associate domain; c-CBL, c-casitas B-lineage lymphoma; VHL, von Hippel-Lindau; LATS1/2, large tumor suppressor homolog 1/2.

Figure 5

The NAE inhibitor MLN4924 has utility in the treatment of lung cancer. It may affect the formation of the TME and promote tumor cell death by regulating a variety of proteins and various signaling pathways, such as the HIF pathway and NF-κB pathway. MLN4924 may also be combined with certain drugs to make chemotherapy and radiotherapy more effective. TME, tumor microenvironment; HIF, hypoxia-inducible factor; DSB, double-strand break; NAE, NEDD8-activating enzyme; mTOR, mammalian target of rapamycin; MDM2, murine double minute 2; RBX1, ring-box 1; Cdt1, chromatin and DNA replication factor 1; NOXA, phorbol-12-myristate-13-acetate-induced protein 1; DR5, death receptor 5; PTX, paclitaxel; CRL, cullin-ring ligase.