MTORC2 suppresses GSK3-dependent snail degradation to positively regulate cancer cell invasion and metastasis

Abstract

mTOR complex 1 (mTORC1) positively regulates cell Snail proteasomal degradation, resulting in eventual Snail invasion and metastasis by enhancing translation of Snail. reduction. Interestingly, inhibition of GSK3 but not SCF/ A connection between mTOR complex 2 (mTORC2) b-TrCP rescued the Snail reduction induced by mTOR and cell invasion and metastasis has also been suggested, inhibitors, suggesting GSK3-dependent, but SCF/b-TrCP–yet the underlying biology or mechanism is largely independent proteasomal degradation of Snail. According-unknown and thus is the focus of this study. Inhibition ly, mTOR inhibitors elevated E-cadherin levels and sup-of mTOR with both mTOR inhibitors and knockdown of pressed cancer cell migration and invasion in vitro and key components of mTORC, including rictor, Sin1, and metastasis in vivo. Collectively, this study reveals that raptor, decreased Snail protein levels. Inhibition of mTOR mTORC2 positively regulates Snail stability to control cell enhanced the rate of Snail degradation, which could be invasion and metastasis. rescued by inhibition of the proteasome. Critically, inhibition of mTORC2 (by knocking down rictor) but not Significance: These findings delineate a new regulation mTORC1 (by knocking down raptor) enhanced Snail deg-mechanism of Snail, an important master regulator of radation. Therefore, only mTORC2 inhibition induces epithelial–mesenchymal transition and invasion in cancers.