Molecular characterization of cadherin expression and function in prostate carcinoma.

摘要

The epithelial cytoarchitecture and function in the prostate gland are maintained in part by the E-cadherin/catenin complex. In human prostate adenocarcinoma, an association between the loss of E-cadherin, increased Gleason score, and extracapsular dissemination has been observed. Further characterizations of human prostate carcinoma cell lines show loss of E-cadherin and expression of N-cadherin in poorly differentiated prostate carcinoma cell lines. N-cadherin expression correlates with an invasive phenotype in cancer cells and mediates the interactions between malignant tumor cells and N-cadherin expressing cells, such as prostate stromal fibroblasts. Additionally, N-cadherin-mediated intercellular adhesions generate a compensatory mechanism that promotes anchorage-independent growth and suppresses apoptosis through a phosphatidylinositol 3-kinase/Akt/protein kinase B survival pathway. Activated Akt results in the phosphorylation of two downstream substrates, Bad and CREB, to regulate Bcl-2 protein stability and bcl-2 transcription, respectively. Under serum deprivation, N-cadherin intercellular adhesion stimulates a 4-fold increase in bcl-2 mRNA expression resulting in a 3.5-fold increase in Bcl-2 protein expression, while the cellular level of proapoptotic protein Bax remains constant. Following N-cadherin homophilic adhesion the phosphatidylinositol 3-kinase p85 subunit is found in immunoprecipitates of the N-cadherin/catenin complex. The recruitment of phosphatidylinositol 3-kinase is dependent on both N-cadherin homophilic adhesion and N-cadherin binding to an intact actin cytoskeleton. These results suggest that the association of the N-cadherin/catenin complex with the actin cytoskeleton acts as a scaffold to localize the activation of phosphatidylinositol 3-kinase/Akt signaling pathway at adherens junctions. The identification of outside-in signal transduction mediated by N-cadherin adhesion provides new information on anti-apoptotic cell-cell adhesion mechanisms enhancing the activity of the phosphatidylinositol 3-kinase/Akt cell survival pathway in metastatic prostate carcinoma. Collectively, these observations indicate that alterations in cadherin expression play a role in prostate cancer progression that may have a profound affect on metastatic cell survival.