Abstract
MLN4924 is a recently discovered small molecule inhibitor of NEDD8-Activating Enzyme (NAE). Because cullin RING ligase (CRL), the largest family of E3 ubiquitin ligase, requires cullin neddylation for its activity, MLN4924, therefore, acts as an indirect inhibitor of CRL by blocking cullin neddylation. Given that CRLs components are up-regulated, whereas neddylation modification is over-activated in a number of human cancers, MLN4924 was found to be effective in growth suppression of cancer cells. Whether MLN4924 is effective against gastric cancer cells, however, remains elusive. Here we showed that in gastric cancer cells, MLN4924 rapidly inhibited cullin 1 neddylation and remarkably suppressed growth and survival as well as migration in a dose-and time-dependent manner. Mechanistic studies in combination with siRNA knockdown-based rescue experiments revealed that MLN4924 induced the accumulation of a number of CRL substrates, including CDT1/ORC1, p21/p27, and PHLPP1 to trigger DNA damage response and induce growth arrest at the G2/M phase, to induce senescence, as well as autophagy, respectively. MLN4924 also significantly suppressed migration by transcriptionally activating E-cadherin and repressing MMP-9. Taken together, our study suggest that neddylation modification and CRL E3 ligase are attractive gastric cancer targets, and MLN4924 might be further developed as a potent therapeutic agent for the treatment of gastric cancer.
Highlights
The Cullin-Ring ligases (CRLs) are the largest multiunit ubiquitin ligases that are responsible for ubiquitylation of about 20% of cellular proteins for targeted degradation[2,3]
We showed that MLN4924 significantly suppressed gastric cancer cell growth by blocking cullin neddylation and subsequent accumulation of a mass of CRL1/SCF E3 substrates, which trigger DNA damage response, G2-M arrest, senescence and autophagy
Our study demonstrated that MLN4924 effectively suppressed proliferation, survival and migration of gastric cancer cells via inactivation of neddylation pathway and CRL1/SCF E3 ligase and that MLN4924 could act as a novel class of anti-cancer agent for the treatment of gastric cancer
Summary
The Cullin-Ring ligases (CRLs) are the largest multiunit ubiquitin ligases that are responsible for ubiquitylation of about 20% of cellular proteins for targeted degradation[2,3]. The full activation of CRLs E3 ligases required cullins neddylation, a reversible modification by adding ubiquitin-like protein NEDD8 (Neural precursor cell expressed developmentally down-regulated 8) to cullins. MLN4924 induces protective autophagy through inducing accumulation of SCF E3 substrates DEPTOR, a direct inhibitor of mTORC1 and the HIF1-REDD1-TSC1 axis, a negative regulatory pathway of mTORC121 All these findings validate neddylation pathway and CRL1/SCF E3 ligase as promising anti-cancer targets, and further demonstrate MLN4924 as a potential drug for cancer therapy. We showed that MLN4924 significantly suppressed gastric cancer cell growth by blocking cullin neddylation and subsequent accumulation of a mass of CRL1/SCF E3 substrates, which trigger DNA damage response, G2-M arrest, senescence and autophagy. Our study demonstrated that MLN4924 effectively suppressed proliferation, survival and migration of gastric cancer cells via inactivation of neddylation pathway and CRL1/SCF E3 ligase and that MLN4924 could act as a novel class of anti-cancer agent for the treatment of gastric cancer
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