Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) positively regulates cell invasion and metastasis via enhancing Snail protein translation. The connection between mTOR complex 2 (mTORC2) and cell invasion and metastasis has also been suggested. However 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 the key components including rictor, Sin1 and raptor of mTORCs decreased Snail protein levels. mTOR inhibitors promoted Snail degradation rate. Moreover, mTOR inhibitor-induced Snail reduction was rescued by proteasome inhibition. Critically, inhibition of mTORC2 (by knocking down rictor), but not mTORC1 (by knocking down raptor), enhanced Snail degradation. Therefore, it is the inhibition of the mTORC2 that induces Snail proteasomal degradation, resulting in eventual Snail reduction. Interestingly, inhibition of GSK3, but not SCF/β-TrCP, rescued Snail reduction induced by mTOR inhibitors, suggesting a GSK3-dependent, but SCF/β-TrCP-independent proteasomal degradation of Snail. Accordingly, mTOR inhibitors elevated E-Cad levels and suppressed cancer cell migration and invasion in vitro and metastasis in vivo. Collectively, the current study has revealed a novel connection between mTORC2 and positive regulation of Snail stability, thus providing a scientific base for mTORC2 in positive regulation of cell EMT, invasion and metastasis. (This study was supported by NIH/NCI R01 CA118450 and CA160522 to SYS and National Natural Science Foundation of China No. 31771578 to QQZ).

Citation Format: Shuo Zhang, Guoqing Qian, Qian-Qian Zhang, Yuying Yao, DongSheng Wang, Zhuo G. Chen, Lijing Wang, Mingwei Chen, Shi-Yong Sun. mTORC2 suppresses GSK3-dependent, but b-TrCP-independent, Snail degradation, contributing to positive regulation of cancer cell invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4598.