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Molecular Endocrinology, doi:10.1210/me.2004-0342
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Molecular Endocrinology 19 (10): 2564-2578
Copyright © 2005 by The Endocrine Society

Formation of E-Cadherin-Mediated Cell-Cell Adhesion Activates Akt and Mitogen Activated Protein Kinase via Phosphatidylinositol 3 Kinase and Ligand-Independent Activation of Epidermal Growth Factor Receptor in Ovarian Cancer Cells

Pradeep Reddy1, Lian Liu1, Chong Ren1, Peter Lindgren, Karin Boman, Yan Shen, Eva Lundin, Ulrika Ottander, Miia Rytinki and Kui Liu

Departments of Medical Biochemistry and Biophysics (P.R., L.L., C.R., Y.S., M.R., K.L.), Clinical Science/Obstetrics and Gynecology (P.L., U.O.), Radiation Sciences (K.B.), and Medical Biosciences (E.L.), Umeå University, SE-901 87, Umeå, Sweden

Address all correspondence and requests for reprints to: Dr. Kui Liu, Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden. E-mail: kui.liu{at}medchem.umu.se.

E-cadherin is a well characterized adhesion molecule that plays a major role in epithelial cell adhesion. Based on findings that expression of E-cadherin is frequently lost in human epithelial cancers, it has been implicated as a tumor suppressor in carcinogenesis of most human epithelial cancers. However, in ovarian cancer development, our data from the current study showed that E-cadherin expression is uniquely elevated in 86.5% of benign, borderline, and malignant ovarian carcinomas irrespective of the degree of differentiation, whereas normal ovarian samples do not express E-cadherin. Thus, we hypothesize that E-cadherin may play a distinct role in the development of ovarian epithelial cancers. Using an E-cadherin-expressing ovarian cancer cell line OVCAR-3, we have demonstrated for the first time that the establishment of E-cadherin mediated cell-cell adhesions leads to the activation of Akt and MAPK. Akt activation is mediated through the activation of phosphatidylinositol 3 kinase, and both Akt and MAPK activation are mediated by an E-cadherin adhesion-induced ligand-independent activation of epidermal growth factor receptor. We have also demonstrated that suppression of E-cadherin function leads to retarded cell proliferation and reduced viability. We therefore suggest that the concurrent formation of E-cadherin adhesion and activation of downstream proliferation signals may enhance the proliferation and survival of ovarian cancer cells. Our data partly explain why E-cadherin is always expressed during ovarian tumor development and progression.




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