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

Mol Endocrinol. 2005 Oct;19(10):2564-78. doi: 10.1210/me.2004-0342. Epub 2005 May 31.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / metabolism*
  • Cell Adhesion / physiology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Enzyme Activation
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Humans
  • In Vitro Techniques
  • MAP Kinase Signaling System
  • Middle Aged
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Ovary / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt

Substances

  • Cadherins
  • Proto-Oncogene Proteins
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases