Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells.
Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells.
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Neddylation 抑制剂 MLN4924 抑制人胃癌细胞的生长和迁移
DOI：
10.1038/srep24218
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发表时间：
2016-04-11
影响因子：
4.6
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Lan H;Tang Z;Jin H;Sun Y
MLN4924是新近发现的一种NEDD8激活酶(NAE)的小分子抑制剂。由于E3泛素连接酶中最大的家族--CRL的活性需要剔除，因此MLN4924通过阻断CRL的活性间接抑制CRL的活性。鉴于CRLS组分上调，而代谢修饰在一些人类癌症中过度激活，MLN4924被发现有效地抑制癌细胞的生长。然而，MLN4924是否对胃癌细胞有效仍不清楚。在这里，我们发现MLN4924以剂量和时间依赖的方式迅速抑制胃癌细胞中cullin 1的降解，显著抑制细胞的生长、存活和迁移。机制研究结合siRNA敲除的抢救实验表明，MLN4924诱导CDT1/ORC1、p21/p27和PHLPP1等CRL底物的积累，分别触发DNA损伤反应和诱导生长停滞在G2/M期，从而诱导衰老和自噬。MLN4924还通过在转录上激活E-钙粘蛋白和抑制基质金属蛋白酶-9而显著抑制迁移。综上所述，我们的研究表明，核苷酸修饰和CRL E3连接酶是有吸引力的胃癌靶点，MLN4924可能进一步开发为治疗胃癌的有效药物。
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.