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Article: P70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells

TitleP70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells
Authors
Keywordsactin
Cdc42
ovarian cancer
p70 S6 kinase
Rac1
Issue Date2011
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2011, v. 30 n. 21, p. 2420-2432 How to Cite?
AbstractOvarian 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. © 2011 Macmillan Publishers Limited All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/136254
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant CouncilHKU 7599/05M
HKU
Funding Information:

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).

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorIp, CKMen_HK
dc.contributor.authorCheung, ANYen_HK
dc.contributor.authorNgan, HYSen_HK
dc.contributor.authorWong, ASTen_HK
dc.date.accessioned2011-07-27T02:11:45Z-
dc.date.available2011-07-27T02:11:45Z-
dc.date.issued2011en_HK
dc.identifier.citationOncogene, 2011, v. 30 n. 21, p. 2420-2432en_HK
dc.identifier.issn0950-9232en_HK
dc.identifier.urihttp://hdl.handle.net/10722/136254-
dc.description.abstractOvarian 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. © 2011 Macmillan Publishers Limited All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_HK
dc.relation.ispartofOncogeneen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectactinen_HK
dc.subjectCdc42en_HK
dc.subjectovarian canceren_HK
dc.subjectp70 S6 kinaseen_HK
dc.subjectRac1en_HK
dc.subject.meshActins - metabolism - ultrastructure-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCell Movement-
dc.subject.meshCytoskeleton - metabolism - ultrastructure-
dc.subject.meshRibosomal Protein S6 Kinases, 70-kDa - genetics - metabolism-
dc.titleP70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0950-9232&volume=30&issue=21&spage=2420&epage=2432&date=2011&atitle=p70+S6+kinase+in+the+control+of+actin+cytoskeleton+dynamics+and+directed+migration+of+ovarian+cancer+cells-
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hken_HK
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_HK
dc.identifier.emailWong, AST: awong1@hkucc.hku.hken_HK
dc.identifier.authorityCheung, ANY=rp00542en_HK
dc.identifier.authorityNgan, HYS=rp00346en_HK
dc.identifier.authorityWong, AST=rp00805en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1038/onc.2010.615en_HK
dc.identifier.pmid21258406-
dc.identifier.scopuseid_2-s2.0-79957599658en_HK
dc.identifier.hkuros188954en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79957599658&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume30en_HK
dc.identifier.issue21en_HK
dc.identifier.spage2420en_HK
dc.identifier.epage2432en_HK
dc.identifier.eissn1476-5594-
dc.identifier.isiWOS:000291008000004-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectp70<SUP>S6K</SUP> in human ovarian cancer-
dc.identifier.scopusauthoridIp, CKM=23987652100en_HK
dc.identifier.scopusauthoridCheung, ANY=54927484100en_HK
dc.identifier.scopusauthoridNgan, HYS=34571944100en_HK
dc.identifier.scopusauthoridWong, AST=23987963300en_HK

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