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Conference Paper: p70S6K induces epithelial to mesenchymal transition in human ovarian cancer cells through upregulation of Snail

Titlep70S6K induces epithelial to mesenchymal transition in human ovarian cancer cells through upregulation of Snail
Authors
Issue Date2007
PublisherElsevier Ltd.
Citation
The 14th European Cancer Conference, Barcelona, Spain, 23-27 September 2007. In EJC Supplements, 2007, v. 5 n. 4, p. 316, Abstract no. 5017 How to Cite?
AbstractBackground: Epithelial ovarian cancer is the most lethal gynecological malignancy and is a highly metastatic cancer characterized by widespread peritoneal dissemination and ascites. The 70 kDa S6 kinase (p70S6K) is a downstream effector of the phosphatidylinositol 3-kinase/AKT/mTOR pathway, which is frequently activated in human ovarian cancer. We recently demonstrated a novel role of p70S6K in the invasion of ovarian cancer cells. Since epithelial-to-mesenchymal transition (EMT) is a critical step contributing to tumor invasiveness, we hypothesized that p70S6K activation induced molecular alterations that mediate EMT. Materials and Methods: To examine the roles of p70S6K, constitutively active forms of p70S6K were transfected into the ovarian cancer cell lines, and the consequence of their transfection was investigated. Optical microscopy was used to assess changes in cell morphology and behavior. Western blot, reverse transcription (RT)-PCR, and reporter gene assays were employed to measure the expression and activity of epithelial and mesenchymal markers. Results: We showed that ovarian cancer cells expressed constitutively active p70S6K underwent phenotypic changes consistent with EMT: the cells lost epithelial cell morphology, acquired fibroblast-like properties, and showed reduced intercellular adhesion. Western blot and RT-PCR revealed strong reduction of the epithelial marker E-cadherin expression and activation of mesenchymal markers vimentin and N-cadherin in p70S6Kexpressing cells. Consistently, p70S6K downregulation by small interfering RNA (siRNA) or the specific mTOR/p70S6K inhibitor rapamycin caused the reversion to an epithelial phenotype, in which E-cadherin was relocalized to the plasma membrane. In addition, active p70S6K induced upregulation of Snail, a repressor of E-cadherin and an inducer of the EMT, which could be reverted by siRNA-mediated repression of p70S6K, indicating that p70S6K-induced EMT depends on Snail. We also showed that p70S6K enhanced Snail activity through inactivation of glycogen synthase kinase 3beta (GSK3b), as expression of constitutively active GSK3b blocked p70S6K-dependent Snail activation. Conclusion: Our study indicates, for the first time, that activation of p70S6K mediates EMT through upregulation of Snail via GSK3b. These findings not only expand the spectrum of biological activities of p70S6K but also suggest that therapeutic inhibition of p70S6K may be a useful strategy to control ovarian tumor invasion and metastasis (supported by RGC HKU7599/05M).
Persistent Identifierhttp://hdl.handle.net/10722/114882
ISSN

 

DC FieldValueLanguage
dc.contributor.authorPon, YLen_HK
dc.contributor.authorZhou, Hen_HK
dc.contributor.authorWong, ASTen_HK
dc.date.accessioned2010-09-26T05:20:12Z-
dc.date.available2010-09-26T05:20:12Z-
dc.date.issued2007en_HK
dc.identifier.citationThe 14th European Cancer Conference, Barcelona, Spain, 23-27 September 2007. In EJC Supplements, 2007, v. 5 n. 4, p. 316, Abstract no. 5017-
dc.identifier.issn1878-1217-
dc.identifier.urihttp://hdl.handle.net/10722/114882-
dc.description.abstractBackground: Epithelial ovarian cancer is the most lethal gynecological malignancy and is a highly metastatic cancer characterized by widespread peritoneal dissemination and ascites. The 70 kDa S6 kinase (p70S6K) is a downstream effector of the phosphatidylinositol 3-kinase/AKT/mTOR pathway, which is frequently activated in human ovarian cancer. We recently demonstrated a novel role of p70S6K in the invasion of ovarian cancer cells. Since epithelial-to-mesenchymal transition (EMT) is a critical step contributing to tumor invasiveness, we hypothesized that p70S6K activation induced molecular alterations that mediate EMT. Materials and Methods: To examine the roles of p70S6K, constitutively active forms of p70S6K were transfected into the ovarian cancer cell lines, and the consequence of their transfection was investigated. Optical microscopy was used to assess changes in cell morphology and behavior. Western blot, reverse transcription (RT)-PCR, and reporter gene assays were employed to measure the expression and activity of epithelial and mesenchymal markers. Results: We showed that ovarian cancer cells expressed constitutively active p70S6K underwent phenotypic changes consistent with EMT: the cells lost epithelial cell morphology, acquired fibroblast-like properties, and showed reduced intercellular adhesion. Western blot and RT-PCR revealed strong reduction of the epithelial marker E-cadherin expression and activation of mesenchymal markers vimentin and N-cadherin in p70S6Kexpressing cells. Consistently, p70S6K downregulation by small interfering RNA (siRNA) or the specific mTOR/p70S6K inhibitor rapamycin caused the reversion to an epithelial phenotype, in which E-cadherin was relocalized to the plasma membrane. In addition, active p70S6K induced upregulation of Snail, a repressor of E-cadherin and an inducer of the EMT, which could be reverted by siRNA-mediated repression of p70S6K, indicating that p70S6K-induced EMT depends on Snail. We also showed that p70S6K enhanced Snail activity through inactivation of glycogen synthase kinase 3beta (GSK3b), as expression of constitutively active GSK3b blocked p70S6K-dependent Snail activation. Conclusion: Our study indicates, for the first time, that activation of p70S6K mediates EMT through upregulation of Snail via GSK3b. These findings not only expand the spectrum of biological activities of p70S6K but also suggest that therapeutic inhibition of p70S6K may be a useful strategy to control ovarian tumor invasion and metastasis (supported by RGC HKU7599/05M).-
dc.languageengen_HK
dc.publisherElsevier Ltd.-
dc.relation.ispartofEJC Supplementsen_HK
dc.titlep70S6K induces epithelial to mesenchymal transition in human ovarian cancer cells through upregulation of Snailen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailWong, AST: awong1@hkucc.hku.hken_HK
dc.identifier.authorityWong, AST=rp00805en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1016/S1359-6349(07)71189-8-
dc.identifier.hkuros144159en_HK

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