Abstract
Inhibition of protein neddylation, particularly cullin neddylation, has emerged as a promising anticancer strategy, as evidenced by the antitumor activity in preclinical studies of the Nedd8-activating enzyme (NAE) inhibitor MLN4924. This small molecule can block the protein neddylation pathway and is now in clinical trials. We and others have previously shown that the antitumor activity of MLN4924 is mediated by its ability to induce apoptosis, autophagy and senescence in a cell context-dependent manner. However, whether MLN4924 has any effect on tumor angiogenesis remains unexplored. Here we report that MLN4924 inhibits angiogenesis in various in vitro and in vivo models, leading to the suppression of tumor growth and metastasis in highly malignant pancreatic cancer, indicating that blockage of angiogenesis is yet another mechanism contributing to its antitumor activity. At the molecular level, MLN4924 inhibits Cullin–RING E3 ligases (CRLs) by cullin deneddylation, causing accumulation of RhoA at an early stage to impair angiogenic activity of vascular endothelial cells and subsequently DNA damage response, cell cycle arrest and apoptosis due to accumulation of other tumor-suppressive substrates of CRLs. Furthermore, we showed that inactivation of CRLs, via small interfering RNA (siRNA) silencing of its essential subunit ROC1/RBX1, recapitulates the antiangiogenic effect of MLN4924. Taken together, our study demonstrates a previously unrecognized role of neddylation in the regulation of tumor angiogenesis using both pharmaceutical and genetic approaches, and provides proof of concept evidence for future development of neddylation inhibitors (such as MLN4924) as a novel class of antiangiogenic agents.
Highlights
Tumor suppressor p53 and oncoprotein Hu antigen R (HuR) were recently identified as new neddylation substrates.[7,8] Nedd[8] conjugation inhibited p53 transcriptional activity,[7] but stabilized HuR.[8]
To investigate the role of neddylation in the regulation of angiogenesis, we first determined the effect of neddylation inactivation with MLN4924 using the in vitro rat aortic ring assay that recapitulates all of the key steps of angiogenesis
We describe a study that shows that protein neddylation plays a role in abnormal angiogenesis, since targeting this protein modification with pharmacological and small interfering RNA (siRNA) agents can suppress tumor angiogenesis
Summary
Tumor suppressor p53 and oncoprotein Hu antigen R (HuR) were recently identified as new neddylation substrates.[7,8] Nedd[8] conjugation inhibited p53 transcriptional activity,[7] but stabilized HuR.[8]. A feature of solid tumors,[29,30] promotes tumor growth and metastasis, and disrupting this process serves as a promising strategy for cancer therapy.[29,31,32] the effect of MLN4924 on the malignant phenotypes of cancer cells has been intensively investigated, its efficacy on tumor angiogenesis and the mechanism(s) underlying this effect remain unexplored. In an attempt to test this idea, we carried out a set of angiogenesis assays in vitro and in vivo, and found that MLN4924 suppresses tumor angiogenesis by inhibiting cullin neddylation and inactivating CRL E3 ligases. Our study identified neddylation as a molecular event important for tumor angiogenesis and provided evidence for targeting this process, such as with MLN4924, as a novel antiangiogenic cancer therapy
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