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E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

Oncogene volume 30, pages 2753–2766 (2011)Cite this article

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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.

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Acknowledgements

We thank Dr H Clevers (University Hospital, the Netherlands), Dr E Fearon (University of Michigan School of Medicine, Detroit, MI, USA), Dr A Passaniti (University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA), Dr AH Ross (University of Massachusetts Medical School, Worcester, MA, USA), Dr V Stambolic (Ontario Cancer Institute, Toronto, Ontario, Canada), Dr RA Weinberg (Massachusetts Institute of Technology, Cambridge, MA, USA) and Dr J Woodgett (Ontario Cancer Institute) for kindly and generously giving us the constructs. This work was supported by the Canadian Institutes of Health Research (PCKL). PCKL is recipient of a Distinguished Scientist Award from the Child and Family Research Institute and MTL is the recipient of a Graduate Studentship Award from the Interdisciplinary Women's Reproductive Health Research Training Program.

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  1. Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

    M-T Lau, C Klausen & P C K Leung

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Lau, MT., Klausen, C. & Leung, P. E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression. Oncogene 30, 2753–2766 (2011). https://doi.org/10.1038/onc.2011.6

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