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 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.
Highlights
Ovarian cancer is a highly metastatic cancer
We show for the first time a role for p70 S6 kinase (p70S6K) in epithelial to mesenchymal transition (EMT) of human ovarian cancer cells
We show that p70S6K, which is frequently activated in ovarian carcinoma cells, is a critical mediator of EMT
Summary
P70S6K is activated by a number of growth factors including epidermal growth factor and hepatocyte growth factor (HGF), which are potent inducers of p70S6K, in ovarian cancer cells [7, 8]. These observations underlie the importance of understanding the role of p70S6K in ovarian cancer. In addition to its well-documented role in cell survival, our recent findings show for the first time that p70S6K may be involved in other aspects of ovarian tumor progression, including invasion and metastasis [8,9,10]. We present evidence suggesting that this tumorigenic activity is associated with the ability of p70S6K to repress E-cadherin through mechanisms that modulate the expression, localization, and function of Snail
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