title: E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression.
abstract: E-cadherin is a cell-cell adhesion protein and tumor suppressor that is silenced in many malignancies. E-cadherin is thought to suppress tumor cell growth by antagonizing β-catenin signaling. However, the role of E-cadherin in ovarian cancer progression is still controversial. In this study, we showed that loss of E-cadherin induced ovarian cancer cell growth and constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by the inhibition of phosphatase and tensin homolog (PTEN) transcription through the downregulation of early growth response gene 1 (Egr1). In addition, immunofluorescence microscopy and T-cell factor promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear β-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear β-catenin signaling by inactivating glycogen synthase kinase-3β indicating cross-talk between the PI3K/Akt and β-catenin signaling pathways. Finally, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via β-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling by antagonizing β-catenin-Egr1-mediated repression of PTEN expression. Thus, the loss of E-cadherin itself may contribute to dysregulated PI3K/Akt signaling through its effects on PTEN, or it may exacerbate the frequent activation of PI3K/Akt signaling that occurs as a result of overexpression, mutation and/or amplification.
authors.affiliation: Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M-T
authors.initials: MT
authors.lastname: Lau
authors.forename: C
authors.initials: C
authors.lastname: Klausen
authors.forename: P C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D015820:Cadherins / Q000502:physiology*; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014158:Transcription, Genetic; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495270:CTNNB1 protein, human; D015820:Cadherins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human