E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells.
E-cadherin (cadh), a member of a family of integral membrane glycoproteins that represent the major component of adherens junctions (AJs), mediates cell-cell adhesion through the calcium-dependent homophilic interaction of its extracellular domain. Metastatic human carcinomas frequently lose E-cadh expression, whereas epithelial ovarian cancer (EOCs) maintain properties characteristic of Müllerian epithelium during tumor progression, including E-cadh expression. Here, we examined the potential role of cell-cell contacts in EOCs through E-cadh homophilic interactions in PI3K/AKT activation whose altered signaling has been implicated in EOC pathogenesis. We show that E-cadh is predominantly expressed at cell-cell contacts and its functionality is necessary and sufficient for the activation of the PI3K/AKT pathway. E-cadh knockdown and phosphoinositide-3-kinase (PI3K) inhibition complement each other in impairing cell-cycle progression and proliferation of ovarian carcinoma cells. E-cadh is stably bound to the PI3K complex, and the de novo formation of E-cadh/beta-catenin complexes following calcium deprivation and subsequent calcium restoration recruits the PI3K p85 subunit to the site of the cell-cell contacts. The finding that E-cadh-mediated AJ formation contributes to PI3K/AKT activation in EOC cells by a mechanism that appears to be restricted to these cells provides the underpinning for therapeutic strategies that exploit PI3K inhibition to halt EOCs.
De Santis
G
G
Unit of Molecular Therapies, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Miotti
S
S
Mazzi
M
M
Canevari
S
S
Tomassetti
A
A
D022005:Adherens Junctions / Q000201:enzymology*; D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction
D015820:Cadherins; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium