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p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells

Oncogene volume 30, pages 2420–2432 (2011)Cite this article

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Abstract

Ovarian cancer is highly metastatic with a poor prognosis. The serine/threonine kinase, p70 S6 kinase (p70S6K), which is a downstream effector of phosphatidylinositol 3-kinase/Akt pathway, is frequently activated in ovarian cancer. Here, we show that p70S6K is a critical regulator of the actin cytoskeleton in the acquisition of the metastatic phenotype. This regulation is through two important activities: p70S6K acts as an actin filament cross-linking protein and as a Rho family GTPase-activating protein. Ectopic expression of constitutively active p70S6K in ovarian cancer cells induced a marked reorganization of the actin cytoskeleton and promoted directional cell migration. Using cosedimentation and differential sedimentation assays, p70S6K was found to directly bind to and cross-link actin filaments. Immunofluorescence studies showed p70S6K colocalized with cytochalasin D-sensitive actin at the leading edge of motile cells. The p70S6K did not affect the kinetics of spontaneous actin polymerization, but could stabilize actin filaments by the inhibition of cofilin-induced actin depolymerization. In addition, we showed that p70S6K stimulated the rapid activation of both Rac1 and Cdc42, and their downstream effector p21-activated kinase (PAK1), but not RhoA. Depletion of p70S6K expression or inhibition of its activity resulted in significant inhibition of actin cytoskeleton reorganization and reduced migration, with a concomitant reduction in Rac1, Cdc42 and PAK1 activation, confirming that the effect was p70S6K specific. Similarly, the actin cytoskeleton reorganization/migratory phenotype could be reversed by expression of dominant negative Rac1 and Cdc42, or inhibition of PAK1. These results reveal a new direction for understanding the oncogenic roles of p70S6K in tumor progression.

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Acknowledgements

We thank Dr N Auersperg, G Thomas and A Hall for providing cell lines and cDNA constructs. This work was supported by the Research Grant Council grant HKU 7599/05M and the HKU Outstanding Young Research Award (AST Wong).

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Authors and Affiliations

  1. School of Biological Sciences, University of Hong Kong, Hong Kong

    C K M Ip & A S T Wong

  2. Department of Pathology, University of Hong Kong, Hong Kong

    A N Y Cheung

  3. Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong

    H Y S Ngan

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  1. C K M Ip
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  2. A N Y Cheung
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  4. A S T Wong
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Correspondence to A S T Wong.

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Ip, C., Cheung, A., Ngan, H. et al. p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells. Oncogene 30, 2420–2432 (2011). https://doi.org/10.1038/onc.2010.615

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