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

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Titlep70 S6 kinase promotes epithelial to mesenchymal transition through snail induction in ovarian cancer cells
AuthorsPon, YL1
Zhou, HY1
Cheung, ANY1
Ngan, HYS1
Wong, AST1
Issue Date2008
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
CitationCancer Research, 2008, v. 68 n. 16, p. 6524-6532 [How to Cite?]
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-07-6302
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.
ISSN0008-5472
2011 Impact Factor: 7.856
2011 SCImago Journal Rankings: 1.309
DOIhttp://dx.doi.org/10.1158/0008-5472.CAN-07-6302
ISI Accession Number IDWOS:000258548200008
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).

ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorPon, YL
dc.contributor.authorZhou, HY
dc.contributor.authorCheung, ANY
dc.contributor.authorNgan, HYS
dc.contributor.authorWong, AST
dc.date.accessioned2010-05-31T04:08:44Z
dc.date.available2010-05-31T04:08:44Z
dc.date.issued2008
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.
dc.description.naturelink_to_OA_fulltext
dc.identifier.citationCancer Research, 2008, v. 68 n. 16, p. 6524-6532 [How to Cite?]
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-07-6302
dc.identifier.citeulike6185080
dc.identifier.doihttp://dx.doi.org/10.1158/0008-5472.CAN-07-6302
dc.identifier.epage6532
dc.identifier.hkuros163467
dc.identifier.hkuros144168
dc.identifier.isiWOS:000258548200008
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).

dc.identifier.issn0008-5472
2011 Impact Factor: 7.856
2011 SCImago Journal Rankings: 1.309
dc.identifier.issue16
dc.identifier.openurl
dc.identifier.pmid18701475
dc.identifier.scopuseid_2-s2.0-53049108469
dc.identifier.spage6524
dc.identifier.urihttp://hdl.handle.net/10722/60343
dc.identifier.volume68
dc.languageeng
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
dc.publisher.placeUnited States
dc.relation.ispartofCancer Research
dc.relation.referencesReferences in Scopus
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 cells
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong