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. 2016 Apr 11;6:24218. doi: 10.1038/srep24218

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Copyright © 2016, Macmillan Publishers Limited

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By inactivating NAE, MLN4924 inhibits CRL E3 ligase activity, leading to accumulation of (a) CDT1/ORC1 to trigger DNA damage response and G2/M arrest; (b) p21/p27 to induce senescence; (c) PHLPP1 to induce autophagy; (d) IκB to inhibit MMP9 and by a unknown mechanism to increase E-cadherin to block migration and invasion. Thus, CRL E3 ligase is valid target and MLN4924 is effective therapeutic agent for the treatment of gastric cancer.