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Abstract
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 the 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 the 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 a NOD-SCID mouse xenograft model. Liver metastasis was evaluated by use of a NOD-scid-IL2Rg-/- mouse model.Results: NAE1 expression was readily detectable in UM. Inhibition of the neddylation pathway by MLN4924 repressed the CSCs properties in UM (capacities of tumorsphere formation and serially replating, aldehyde dehydrogenase-positive cells, and frequency of CSC) through Slug protein degradation. MLN4924 treatment disturbed the paracrine secretion of NF-κB-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. Clin Cancer Res; 24(15); 3741-54. ©2017 AACRSee related commentary by Yang et al., p. 3477.
Highlights
Metastasis is the major and direct cause of death in patients with cancer at the terminal stage
The inhibitory effect of neddylation blockade on proliferation, which was confirmed by xenografted uveal melanoma (UM) tumor in NOD-SCID mice, was involved in activation of Ataxia telangiectasia-mutated (ATM)-checkpoint kinase 1 (Chk1)-Cdc25C DNA damage response, and G2–M phase arrest
Western blotting results indicated that the levels of NAE1, UBA3, and UBC12 were higher in the human UM cells than those in ARPE-19 cells (Fig. 1A)
Summary
Metastasis is the major and direct cause of death in patients with cancer at the terminal stage. There are no effective therapies for metastatic patients. The complicated metastasis process is principally composed of intravasation, circulation, extravasation, and colonization in the target organ [1]. Intravasation is referred to as the process that the cancer cells in the primary tumor sites break out of physical barriers in the surrounding tissues, and enter the blood or lymphatic stream to become circulating tumor cells A small portion of CTCs that acquire stemness features can successfully escape anoikis, immune response, and shear stress [2]. The CTCs undergo extravasation in which they leave from the bloodstream for distant organs and tissues, where they are called metastasis
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