Potential diagnostic and therapeutic targets and anti-tumor mechanisms of Neddylation pathway in digestive system tumors / 中华检验医学杂志

Neddylation,a novel post-translational modification of proteins, is overactivated in digestive system tumors and can be used as a potential anti-tumor molecular target. Targeting Neddylation pathway plays an anti-tumor role by inducing cell cycle arrest, apoptosis, senescence and autophagy of digestive system tumor cells, as well as enhancing the sensitivity of digestive system tumor cells to the radiotherapy and chemotherapy. Targeting Neddylation pathway and its inhibnitor MLN4924 can act as poential targets against digestive system tumors.

Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1

The primary cilium is a microtubule-based sensory organelle. The molecular mechanism that regulates ciliary dynamics remains elusive. Here, we report an unexpected finding that MLN4924, a small molecule inhibitor of NEDD8-activating enzyme (NAE), blocks primary ciliary formation by inhibiting synthesis/assembly and promoting disassembly. This is mainly mediated by MLN4924-induced phosphorylation of AKT1 at Ser473 under serum-starved, ciliary-promoting conditions. Indeed, pharmaceutical inhibition (by MK2206) or genetic depletion (via siRNA) of AKT1 rescues MLN4924 effect, indicating its causal role. Interestingly, pAKT1-Ser activity regulates both ciliary synthesis/assembly and disassembly in a MLN4924 dependent manner, whereas pAKT-Thr determines the ciliary length in MLN4924-independent but VHL-dependent manner. Finally, MLN4924 inhibits mouse hair regrowth, a process requires ciliogenesis. Collectively, our study demonstrates an unexpected role of a neddylation inhibitor in regulation of ciliogenesis via AKT1, and provides a proof-of-concept for potential utility of MLN4924 in the treatment of human diseases associated with abnormal ciliogenesis.

Effects of NEDD8 covalent modification inhibitor MLN4924 on proliferation and apoptosis of human ovarian cancer cell line SKOV3 / 中国免疫学杂志

Objective:To explore the effects of neural precursor cell-expressed developmentally down regulated 8(NEDD8) covalent modification on ovarian cancer cell proliferation and apoptosis,and the possible underlying mechanisms.Methods:Use different concentrations of MLN4924 (0,0.125,0.25,0.5 mol/L) and human ovarian cancer cell line SKOV3,the expression levels of PAR3, HER2,Neddylated-cullins,P-IκBα were detected by Western blot and the secretion of IL-6 was measured by ELISA after 4 h treatment.The cell proliferation was determined by CCK-8 staining and the cell cycle and apoptosis were analyzed by flow cytometry after 72 h treatment.Results:MLN4924 inhibits the proliferation of SKOV3 cells in a dose-dependent manner,which is associated with reduced IL-6 secretion.Western blot revealed that MLN4924 dose-dependently inhibits the neddylation of cullins(reduced neddylated-cullins) and induced the accumulation of P-IκBα,whereas the expression levels of PARs and HER2 remained largely unchanged.At the same time MLN4924 dose-dependently induced cell cycle prove at S phase and the formation of a large number of tetraploids.Furthermore,apoptosis increased with the dose of MLN4924.Conclusion:NEDD8 covalent modification specific inhibitor MLN4924 can significantly inhibit the proliferation of SKOV3 cells and induce cell cycle arrest and apoptosis.The above inhibitory effects may partially result from impaired P-IκBα degradation and IL-6 secretion.

The Nedd8-activating enzyme inhibitor MLN4924 suppresses colon cancer cell growth via triggering autophagy

Neddylation is a post-translational protein modification process. MLN4924 is a newly discovered pharmaceutical neddylation inhibitor that suppresses cancer growth with several cancer types. In our study, we first investigated the effect of MLN4924 on colon cancer cells (HCT116 and HT29). MLN4924 significantly inhibited the neddylation of cullin-1 and colon cancer cell growth in a time and dose-dependent manner. MLN4924 induced G2/M cell cycle arrest and apoptosis in HCT116 and HT29 cells. Moreover, MLN4924 also triggered autophagy in HCT116 and HT29 cells via suppressing the PI3K/AKT/mTOR pathway. Inhibiting autophagy by autophagy inhibitor 3-MA or ATG5 knockdown reversed the function of MLN4924 in suppressing colon cancer cell growth and cell death. Interestingly, MLN4924 suppresses colon cell growth in a xenograft model. Together, our finding revealed that blocking neddylation is an attractive colon cancer therapy strategy, and autophagy might act as a novel anti-cancer mechanism for the treatment of colon cancer by MLN4924.

The mechanism of MLN4924 for anticancer therapy / 国际肿瘤学杂志

MLN4924 can inhibit the proliferation,invasion and metastasis of tumor by inducing tumor cells apoptosis,senescence and autophagy,which can inhibit tumor angiogenesis and enhance the sensitivity of radiotherapy and chemotherapy.Therefore,MLN4924 plays a good anti-tumor effect.