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Article: p70 S6 kinase promotes epithelial to mesenchymal transition through snail induction in ovarian cancer cells

Titlep70 S6 kinase promotes epithelial to mesenchymal transition through snail induction in ovarian cancer cells
Authors
Issue Date2008
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2008, v. 68 n. 16, p. 6524-6532 How to Cite?
Abstractp70 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 interferencemediated 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. © 2008 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/60343
ISSN
2014 Impact Factor: 9.329
2013 SCImago Journal Rankings: 5.627
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants Council7599/05M
Funding Information:

Grant support: Hong Kong Research Grants Council Grant 7599/05M (A.S.T. Wong).

References

 

DC FieldValueLanguage
dc.contributor.authorPon, YLen_HK
dc.contributor.authorZhou, HYen_HK
dc.contributor.authorCheung, ANYen_HK
dc.contributor.authorNgan, HYSen_HK
dc.contributor.authorWong, ASTen_HK
dc.date.accessioned2010-05-31T04:08:44Z-
dc.date.available2010-05-31T04:08:44Z-
dc.date.issued2008en_HK
dc.identifier.citationCancer Research, 2008, v. 68 n. 16, p. 6524-6532en_HK
dc.identifier.issn0008-5472en_HK
dc.identifier.urihttp://hdl.handle.net/10722/60343-
dc.description.abstractp70 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 interferencemediated 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. © 2008 American Association for Cancer Research.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_HK
dc.relation.ispartofCancer Researchen_HK
dc.subject.meshCell Differentiation-
dc.subject.meshEpithelial Cells - metabolism - pathology-
dc.subject.meshMesoderm - metabolism - pathology-
dc.subject.meshOvarian Neoplasms - genetics - metabolism - pathology-
dc.subject.meshRibosomal Protein S6 Kinases, 70-kDa - physiology-
dc.titlep70 S6 kinase promotes epithelial to mesenchymal transition through snail induction in ovarian cancer cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0008-5472&volume=68&issue=16&spage=6524&epage=6532&date=2008&atitle=p70+S6+kinase+promotes+epithelial+to+mesenchymal+transition+through+snail+induction+in+ovarian+cancer+cells.en_HK
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.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1158/0008-5472.CAN-07-6302en_HK
dc.identifier.pmid18701475en_HK
dc.identifier.scopuseid_2-s2.0-53049108469en_HK
dc.identifier.hkuros163467en_HK
dc.identifier.hkuros144168-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-53049108469&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume68en_HK
dc.identifier.issue16en_HK
dc.identifier.spage6524en_HK
dc.identifier.epage6532en_HK
dc.identifier.eissn1538-7445-
dc.identifier.isiWOS:000258548200008-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridPon, YL=22235406500en_HK
dc.identifier.scopusauthoridZhou, HY=24802759600en_HK
dc.identifier.scopusauthoridCheung, ANY=54927484100en_HK
dc.identifier.scopusauthoridNgan, HYS=34571944100en_HK
dc.identifier.scopusauthoridWong, AST=23987963300en_HK
dc.identifier.citeulike6185080-

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