MLN4924, a protein neddylation inhibitor, elicits antitumor effect via suppression of angiogenesis

In the process of tumorigenesis, angiogenesis provide oxygen and nutrients for tumor progression. Anti-angiogenesis has become a promising target of cancer therapy. Cullin-RING ligases (CRLs) are a cullin scaffold RING-finger domain containing E3 and are involved in the ubiquitination of specific substrates which regulate important biological processes. The holoenzyme E3 activity of CRLs is controlled by NEDD8. A novel NEDD8-activating enzyme inhibitor, MLN4924, is reported to block the neddylation of cullins and elicits antitumor effect. MLN4924 has been reported to be assoiciated with antiangiogenesis. In this study, we aim to investigate the role of anti-angiogensis in the antitumor effect of MLN4924. Our results showed that MLN4924 induces the cell cycle arrest, apoptosis and suppresses the cell viability and migration in human umbilical vein endothelial cells (HUVECs). Moreover, MLN4924 inhibits angiogenesis in Matrigel plug assay in vivo and tube-formation assay in vitro. Anti-angiogesis was involved in the antitumor effect on human urothelial carcinoma cells (T24) and colon cancer cells in vivo xenograft model. MLN4924 suppressed the VEGF-mediated VEGFR2 downstream activation. Note: This abstract was not presented at the meeting. Citation Format: Kuan-Lin Kuo, Shao-Ping Yang, Shih-Ming Liao, Yeong-Shiau Pu, Kuo-How Huang. MLN4924, a protein neddylation inhibitor, elicits antitumor effect via suppression of angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4439.