AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation.
AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation.
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DOI：
10.1158/0008-5472.can-15-1941
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发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Hung MC
中科院分区：
文献类型：
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作者：
Li CW;Xia W;Lim SO;Hsu JL;Huo L;Wu Y;Li LY;Lai CC;Chang SS;Hsu YH;Sun HL;Kim J;Yamaguchi H;Lee DF;Wang H;Wang Y;Chou CK;Hsu JM;Lai YJ;LaBaff AM;Ding Q;Ko HW;Tsai FJ;Tsai CH;Hortobagyi GN;Hung MC
上皮间质转化（EMT）是促进癌细胞迁移、侵袭和转移的重要生理过程。来自细胞和遗传学研究的多项证据表明，AKT1/PKBα（而非 AKT2 或 AKT3）充当 EMT 和乳腺癌转移的负调节因子。然而，AKT1 抑制 EMT 的潜在机制仍不清楚。在这里，我们证明 AKT1 对 Twist1 的磷酸化是 β-TrCP 介导的 Twist1 泛素化和降解所必需的。临床使用的AKT抑制剂MK-2206对AKT1具有更高的特异性，稳定Twist1并增强乳腺癌细胞的EMT。然而，我们发现白藜芦醇（一种天然存在的化合物）可诱导 β-TrCP 介导的 Twist1 降解，从而减弱乳腺癌细胞中 MK-2206 诱导的 EMT。综上所述，我们的研究结果表明，白藜芦醇可以抵消抗 AKT 治疗引起的意外转移潜力，因此表明在抗 AKT 治疗方案中添加白藜芦醇可能为限制 EMT 提供额外支持。
Epithelial-to-mesenchymal transition (EMT) is an essential physiological process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKBα, but not AKT2 or AKT3, serves as a negative regulator of EMT and breast cancer metastasis. However, the underlying mechanism by which AKT1 suppresses EMT remains poorly defined. Here, we demonstrate that phosphorylation of Twist1 by AKT1 is required for β-TrCP-mediated Twist1 ubiquitination and degradation. The clinically used AKT inhibitor MK-2206, which possesses higher specificity toward AKT1, stabilized Twist1 and enhanced EMT in breast cancer cells. However, we discovered that resveratrol, a naturally occurring compound, induced β-TrCP-mediated Twist1 degradation to attenuate MK-2206-induced EMT in breast cancer cells. Taken together, our findings demonstrate that resveratrol counteracts the unexpected metastatic potential induced by anti-AKT therapy, and therefore suggest that the addition of resveratrol to an anti-AKT therapeutic regimen may provide extra support for limiting EMT.