Neddylation blockade diminishes hepatic metastasis by dampening cancer stem-like cells and angiogenesis in uveal melanoma

Purpose: Liver metastasis is the major and direct cause of death in patients with uveal melanoma (UM). There is no effective therapy for patients with metastatic UM. Improved treatments of hepatic metastatic patients with UM were urgently needed. Inspired by readily detectable key components in neddylation pathway in UM cells, we aimed at exploring whether neddylation pathway was a therapeutic target for liver metastatic UM. Experimental Design: Expression of key proteins in neddylation pathway in UM was detected by Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunohistochemical staining. Cellular proliferation, apoptosis, cell cycle, migration, and cancer stem-like cells (CSCs) properties were examined upon treatment with MLN4924, a potent and selective NAE inhibitor. Antitumor activity and frequency of CSCs were determined by using NOD-SCID mouse xenograft model. Liver metastasis was evaluated by use of a NOD-scid-IL2Rg–(NSI) mouse model. Results: NAE1 expression was readily detectable in UM. Inhibition of neddylation pathway by MLN4924 repressed the CSCs properties in UM [capacities of tumorsphere formation and serially-replating, aldehyde dehydrogenase positive (ALDH+) cells, and frequency of CSCs] through Slug protein degradation. MLN4924 treatment disturbed the paracrine secretion of NF-B-mediated VEGF-C and its dependent angiogenesis. The inhibitory effect of neddylation blockade on proliferation which was confirmed by xenografted UM tumor in NOD-SCID mice was involved in activation of ATM-Chk1-Cdc25C DNA damage response, and G2/M-phase arrest. Neddylation inhibition profoundly inhibited hepatic metastasis in UM. Conclusions: Our studies validate the neddylation pathway as a promising therapeutic target for the treatment of patients with hepatic metastasis of UM.

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