mTORC2 Suppresses GSK3-Dependent Snail Degradation to Positively Regulate Cancer Cell Invasion and Metastasis
mTORC2 Suppresses GSK3-Dependent Snail Degradation to Positively Regulate Cancer Cell Invasion and Metastasis
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mTORC2 抑制 GSK3 依赖性蜗牛降解，积极调节癌细胞侵袭和转移
DOI：
10.1158/0008-5472.can-19-0180
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发表时间：
2019
期刊：
影响因子：
11.2
通讯作者：
Sun Shi-Yong
中科院分区：
文献类型：
--
作者：
Zhang Shuo;Qian Guoqing;Zhang Qian-Qian;Yao Yuying;Wang Dongsheng;Chen Zhuo G.;Wang Li-Jing;Chen Mingwei;Sun Shi-Yong
mTOR复合物1（mTORC 1）通过增强Snail的翻译而正调控细胞侵袭和转移。mTOR复合物2（mTORC 2）与细胞侵袭和转移之间的联系也被提出，但潜在的生物学或机制在很大程度上是未知的，因此是本研究的重点。用mTOR抑制剂和mTORC的关键组分（包括rictor、Sin 1和raptor）的敲低来抑制mTOR，可降低Snail蛋白水平。mTOR的抑制增强了Snail降解的速率，这可以通过抑制蛋白酶体来挽救。重要的是，抑制mTORC 2（通过敲低rictor）而不是mTORC 1（通过敲低raptor）增强了Snail降解。因此，只有mTORC 2抑制诱导Snail蛋白酶体降解，最终导致Snail减少。有趣的是，GSK 3而不是SCF/β-TrCP的抑制挽救了由mTOR抑制剂诱导的Snail减少，表明Snail的GSK 3依赖性但SCF/β-TrCP非依赖性蛋白酶体降解。因此，mTOR抑制剂升高E-钙粘蛋白水平并抑制癌细胞的体外迁移和侵袭以及体内转移。总之，本研究揭示了mTORC 2正调控Snail的稳定性以控制细胞的侵袭和转移。
mTOR complex 1 (mTORC1) positively regulates cell invasion and metastasis by enhancing translation of Snail. A connection between mTOR complex 2 (mTORC2) and cell invasion and metastasis has also been suggested, yet the underlying biology or mechanism is largely unknown and thus is the focus of this study. Inhibition of mTOR with both mTOR inhibitors and knockdown of key components of mTORC, including rictor, Sin1, and raptor, decreased Snail protein levels. Inhibition of mTOR enhanced the rate of Snail degradation, which could be rescued by inhibition of the proteasome. Critically, inhibition of mTORC2 (by knocking down rictor) but not mTORC1 (by knocking down raptor) enhanced Snail degradation. Therefore, only mTORC2 inhibition induces Snail proteasomal degradation, resulting in eventual Snail reduction. Interestingly, inhibition of GSK3 but not SCF/β-TrCP rescued the Snail reduction induced by mTOR inhibitors, suggesting GSK3-dependent, but SCF/β-TrCP–independent proteasomal degradation of Snail. Accordingly, mTOR inhibitors elevated E-cadherin levels and suppressed cancer cell migration and invasionin vitroand metastasisin vivo. Collectively, this study reveals that mTORC2 positively regulates Snail stability to control cell invasion and metastasis.SignificanceThese findings delineate a new regulation mechanism of Snail, an important master regulator of epithelial–mesenchymal transition and invasion in cancers.