Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy. Cancer Res; 72(13); 3360-71. Ó2012 AACR.

Our study highlights the overactivated neddylation pathway in lung cancer development and as a promising therapeutic target.

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Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition.

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A wheat (Triticum aestivum L.) line 4844 with superior numbers of florets and grains per spike was derived from the cross between Fukohokomugi wheat and Agropyron cristatum (L.) Gaertn. In order to determine the genetic control of floret and kernel number per spike in this line, chromosome addition and substitution lines that were derived from line 4844 were characterized by means of in situ hybridization, microsatellite (SSR), and gliadin analyses. Genomic in situ hybridization analysis with biotinylated P genomic DNA of A. cristatum as a probe demonstrated that the increased number of florets and grains in a spike was associated with the introgression of an A. cristatum chromosome. Fluorescence in situ hybridization, using a repetitive sequence, pAs1, derived from Aegilops squarrosa L., indicated the replacement of chromosome 6D of wheat in the wheat-A. cristatum chromosome substitution lines. This was confirmed by microsatellite analyses with wheat SSR markers specific for chromosome 6D, suggesting that the A. cristatum chromosome was homoeologous to group 6 and was therefore designated as 6P. This conclvsion was further confirmed by amplification using EST-SSR markers and gliadin analysis. The increased number of florets and kernels within a spike of the wheat-A. cristatum hybrids thus was controlled by gene(s) located on A. cristatum chromosome 6P.

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