The Nedd8-activating enzyme inhibitor MLN4924 suppresses colon cancer cell growth via triggering autophagy.

Neddylation is a post-translational protein modification process. MLN4924 is a newly discovered pharmaceutical neddylation inhibitor that suppresses cancer growth with several cancer types. In our study, we first investigated the effect of MLN4924 on colon cancer cells (HCT116 and HT29). MLN4924 significantly inhibited the neddylation of cullin-1 and colon cancer cell growth in a time and dose-dependent manner. MLN4924 induced G2/M cell cycle arrest and apoptosis in HCT116 and HT29 cells. Moreover, MLN4924 also triggered autophagy in HCT116 and HT29 cells via suppressing the PI3K/AKT/mTOR pathway. Inhibiting autophagy by autophagy inhibitor 3-MA or ATG5 knockdown reversed the function of MLN4924 in suppressing colon cancer cell growth and cell death. Interestingly, MLN4924 suppresses colon cell growth in a xenograft model. Together, our finding revealed that blocking neddylation is an attractive colon cancer therapy strategy, and autophagy might act as a novel anti-cancer mechanism for the treatment of colon cancer by MLN4924.

Prognostic impact of the number of lymph nodes examined in different stages of colorectal mucinous adenocarcinoma.

BACKGROUND: Mucinous adenocarcinoma (MC) is a special kind of colorectal adenocarcinoma that occurs more frequently in young patients and females, but the prognostic effect of lymph nodes in MC patients is unclear. This population-based study was conducted to analyze the prognostic value of the number of lymph nodes examined in different stages of colorectal MC. METHODS: We included 17,001 MC patients from the Surveillance, Epidemiology, and End Results program database between 2003 and 2013, of which 12,812 (75%) had >12 lymph nodes examined. RESULTS: Compared to the group with insufficient lymph nodes examined, patients with more lymph nodes (>12) examined tended to come from east and central America, were more frequently female and young, were diagnosed after 2008, had larger-sized tumors of less differentiated grade and in later stages, had not received radiation therapy and had more positive nodal status. Patients with more lymph nodes (>12) examined demonstrated significantly better survival than those with insufficient lymph nodes examined only in stages II and III (stage II: overall, P<0.001; cancer-specific, P<0.001; stage III: overall, P=0.093; cancer-specific, P=0.032), even though the overall (P<0.001) and cancer-specific survival (P<0.001) showed significant differences between the two groups. Both univariate (overall, HR=0.739, 95% CI=0.703-0.777, P<0.001; cancer-specific, HR=0.742, 95% CI=0.698-0.788, P<0.001) and multivariate (overall, HR=0.601, 95% CI=0.537-0.673, P<0.001; cancer-specific, HR=0.582, 95% CI=0.511-0.664, P<0.001) Cox proportional hazards models verified the association between >12 lymph nodes examined and better survival. CONCLUSION: More number of lymph nodes (.12) examined significantly increased the survival probability of MC patients in stages II and III, but had no significant influence on patients in stages I and IV, indicating the effect of number of lymph nodes examined was a stage-dependent prognostic factor in clinical utility.