Hepatocyte growth factor phosphorylates p70 S6 kinase to regulate Rac1 and Cdc42 and promote ovarian cancer cell migration and invasion

Abstract

Ovarian cancer is the most lethal gynecological cancer. The hepatocyte growth factor (HGF) receptor Met is a receptor tyrosine kinase that is frequently overexpressed in ovarian cancer and correlates with poor prognosis. However, the molecular mechanisms responsible are still poorly understood. Our recent findings show for the first time that activation of p70 S6 kinase (p70S6K) downstream of phosphatidylinositol 3-kinase is a key step for HGF-induced invasion and migration of ovarian cancer cells. In this study, we showed that ectopic expression of active p70S6K induced dramatic reorganization of the actin cytoskeleton. This effect was associated with activation of two members of the Rho family of GTPases, Rac1 and Cdc42, but not RhoA. Inhibition of p70S6K by a specific inhibitor or small interfering RNA abolished the HGF-stimulated migratory phenotype with a concomitant reduction in Rac1 and Cdc42 activation, confirming the effect was p70S6K specific. Overexpression of constitutively active forms of Rac1 and Cdc42 were sufficient to induce cell migration, whereas dominant negative mutants of Rac1 and Cdc42 inhibited p70S6K-induced motogenic signal. Importantly, we showed that active p70S6K co-precipitated with F-actin in vitro. Immunofluorescence experiments confirmed that active p70S6K colocalized in vivo with the actin filaments. These results identify a novel mechanism in HGF-induced cellular invasion and migration, which is mediated by p70S6K through regulation of the actin cytoskeleton by Rho GTPases (This work is supported by Hong Kong Research Grants Council Grant HKU7599/05M to A.S.T.W.).