AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation

作者：Li Chia Wei; Xia Weiya; Lim Seung Oe; Hsu Jennifer L; Huo Longfei; Wu Yun; Li Long Yuan; Lai Chien Chen; Chang Shih Shin; Hsu Yi Hsin; Sun Hui Lung; Kim Jongchan; Yamaguchi Hirohito; Lee Dung Fang; Wang Hongmei; Wang Yan; Chou Chao Kai; Hsu Jung Mao; Lai Yun Ju; LaBaff Adam M; Ding Qingqing; Ko How Wen; Tsai Fuu Jen; Tsai Chang Hai; Hortobagyi Gabriel N; Hung Mien Chie

来源：Cancer Research, 2016, 76(6): 1451-1462.

DOI：10.1158/0008-5472.CAN-15-1941

Epithelial-to-mesenchymal transition (EMT) is an essential physiologic process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKB alpha, 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 beta-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 beta 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.

• 出版日期2016-3-15
• 单位中国医科大学