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p70 S6 Kinase Promotes Epithelial to Mesenchymal Transition through Snail Induction in Ovarian Cancer Cells

¹ School of Biological Sciences and Departments of ² Pathology and ³ Obstetrics and Gynecology, University of Hong Kong, Hong Kong

Requests for reprints: Alice S.T. Wong, School of Biological Sciences, University of Hong Kong, 4S-14 Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong. Phone: 852-2299-0865; Fax: 852-2559-9114; E-mail: awong1{at}hku.hk.

Key Words: ovarian cancer • p70 S6 kinase • epithelial-mesenchymal transition • invasion

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 interference–mediated 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. [Cancer Res 2008;68(16):6524–32]