Oncogene, 2011-05, Vol.30 (21), p.2420-2432
2011
Details
- Autor(en) / Beteiligte
- Titel
- p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells
- Ist Teil von
- Oncogene, 2011-05, Vol.30 (21), p.2420-2432
- Ort / Verlag
- Basingstoke: Nature Publishing Group
- Erscheinungsjahr
- 2011
- Link zum Volltext
- Quelle
- Nexis
- Beschreibungen/Notizen
- Ovarian cancer is highly metastatic with a poor prognosis. The serine/threonine kinase, p70 S6 kinase (p70(S6K)), which is a downstream effector of phosphatidylinositol 3-kinase/Akt pathway, is frequently activated in ovarian cancer. Here, we show that p70(S6K) is a critical regulator of the actin cytoskeleton in the acquisition of the metastatic phenotype. This regulation is through two important activities: p70(S6K) acts as an actin filament cross-linking protein and as a Rho family GTPase-activating protein. Ectopic expression of constitutively active p70(S6K) in ovarian cancer cells induced a marked reorganization of the actin cytoskeleton and promoted directional cell migration. Using cosedimentation and differential sedimentation assays, p70(S6K) was found to directly bind to and cross-link actin filaments. Immunofluorescence studies showed p70(S6K) colocalized with cytochalasin D-sensitive actin at the leading edge of motile cells. The p70(S6K) 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 p70(S6K) stimulated the rapid activation of both Rac1 and Cdc42, and their downstream effector p21-activated kinase (PAK1), but not RhoA. Depletion of p70(S6K) 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 p70(S6K) 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 p70(S6K) in tumor progression.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/onc.2010.615Titel-ID: cdi_proquest_miscellaneous_876229588
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Actin, Actins - metabolism, Actins - ultrastructure, AKT protein, Biological and medical sciences, Blotting, Western, Cancer cells, cdc42 GTP-Binding Protein - genetics, cdc42 GTP-Binding Protein - metabolism, Cdc42 protein, Cell Line, Tumor, Cell migration, Cell Movement, Cell physiology, Cell structures and functions, Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes, Cofilin, Cytochalasin D, Cytoskeleton, Cytoskeleton - metabolism, Cytoskeleton - ultrastructure, Cytoskeleton, cytoplasm. Intracellular movements, Depolymerization, Development and progression, Ectopic expression, Enzyme Activation - drug effects, Female, Female genital diseases, Filaments, Fundamental and applied biological sciences. Psychology, Genetic aspects, Green Fluorescent Proteins - genetics, Green Fluorescent Proteins - metabolism, GTPase-activating protein, Gynecology. Andrology. Obstetrics, Hep G2 Cells, Hepatocyte Growth Factor - pharmacology, Humans, Immunofluorescence, Kinases, Medical sciences, Metastases, Metastasis, Microscopy, Electron, Microscopy, Fluorescence, Molecular and cellular biology, Ovarian cancer, p21-activated kinase, p21-Activated Kinases - genetics, p21-Activated Kinases - metabolism, p70 S6 kinase, Phenotypes, Physiological aspects, Protein Binding, Protein kinases, Protein-serine/threonine kinase, rac1 GTP-Binding Protein - genetics, rac1 GTP-Binding Protein - metabolism, Rac1 protein, RhoA protein, Ribosomal Protein S6 Kinases, 70-kDa - genetics, Ribosomal Protein S6 Kinases, 70-kDa - metabolism, RNA Interference, Transfection, Tumor Cells, Cultured, Tumors