p70 S6 kinase promotes epithelial to mesenchymal transition through snail induction in ovarian cancer cells

Abstract

p70 S6 kinase (p70 S6K) is a downstream effector of phosphatidylinositol 3-kinase and is frequently activated in human ovarian cancer. Here we show that p70 S6K functions in epithelial to mesenchymal transition (EMT) responsible for the acquisition of invasiveness during tumor progression. This tumorigenic activity is associated with the ability of p70 S6K to repress E-cadherin through the up-regulation of Snail. p70 S6K activation induced phenotypic changes consistent with EMT in ovarian cancer cells: The cells lost epithelial cell morphology, acquired fibroblast-like properties, and showed reduced intercellular adhesion. Western blot showed that p70 S6K activation led to decreased expression of the epithelial marker E-cadherin and increased expression of mesenchymal markers N-cadherin and vimentin. Inhibition of p70 S6K by a specific inhibitor or small interfering RNA reversed the shift of EMT markers. Importantly, p70 S6K activation also stimulated the expression of Snail, a repressor of E-cadherin and an inducer of EMT, but not other family members such as Slug. This induction of Snail was regulated at multiple levels by increasing transcription, inhibiting protein degradation, and enhancing nuclear localization of Snail. RNA interferencemediated knockdown of Snail suppressed p70 S6K-induced EMT, confirming that the effect was Snail specific. Furthermore, phospho (active)-p70 S6K staining correlated with higher tumor grade. We also showed a significant positive correlation between p70 S6K activation and Snail expression in ovarian cancer tissues. These results indicate that p70 S6K may play a critical role in tumor progression in ovarian cancer through the induction of EMT. Targeting p70 S6K may thus be a useful strategy to impede cancer cell invasion and metastasis. © 2008 American Association for Cancer Research.