Abstract
Associated with the metastatic progression of epithelial tumors is the dynamic regulation of cadherins. Whereas E-cadherin is expressed in most epithelium and carcinomas, recent studies suggest that the up-regulation of other cadherin subtypes in carcinomas, such as N-cadherin, may function in cancer progression. We demonstrate that a signal transduction cascade links the N-cadherin.catenin adhesion complex to up-regulation of the anti-apoptotic protein Bcl-2. In suspension, aggregates of DU-145 cells, an E-cadherin expressing human prostate carcinoma line, survive loss of integrin-dependent adhesion by a different anti-apoptotic signaling pathway than the N-cadherin expressing lines PC3 and PC3N. N-cadherin intercellular adhesion mediates a 3.5-fold increase in Bcl-2 protein expression, whereas the level of the proapoptotic protein Bax remains constant. Only N-cadherin ligation in PC3 cells, which express both N-cadherin and E-cadherin, is sufficient to induce activation of Akt/protein kinase B. N-cadherin homophilic ligation initiates phosphatidylinositol 3-kinase-dependent activation of Akt resulting in Akt phosphorylation of Bad on serine 136. Following N-cadherin homophilic adhesion phosphatidylinositol 3-kinase was identified in immunoprecipitates of the N-cadherin.catenin complex. The recruitment of phosphatidylinositol 3-kinase to the adhesion complex is dependent on ligation of N-cadherin and an organized actin cytoskeleton because cytochalasin D blocks the recruitment. We propose that N-cadherin homophilic adhesion can initiate anti-apoptotic signaling, which enhances the Akt cell survival pathway in metastatic cancer.
Highlights
Associated with the metastatic progression of epithelial tumors is the dynamic regulation of cadherins
N-cadherin Engagement Increases the Bcl-2/Bax Protein Ratio—Because the protein kinase Akt is both a critical regulator of cell survival and one of the downstream substrates activated by PI 3-kinase signaling, we evaluated whether formation of Ca2ϩ-dependent cell-cell adhesion in adherent PC3N cells could affect the activation state of Akt by assessing phosphorylation of Akt on serine 473 (Ser-473) using a phospho-specific antibody (Fig. 2A)
N-cadherin was found in the anti-vinculin immunoprecipitations associated with both -catenin and p120ctn (Fig. 6A). These results suggest that vinculin is present with the N-cadherin1⁄7catenin complex in prostate carcinoma cells similar to what has been observed for E-cadherin in breast cancer cell lines [6], and this interaction may mediate N-cadherin1⁄7catenin binding to the actin cytoskeleton
Summary
Associated with the metastatic progression of epithelial tumors is the dynamic regulation of cadherins. N-cadherin Engagement Increases the Bcl-2/Bax Protein Ratio—Because the protein kinase Akt is both a critical regulator of cell survival and one of the downstream substrates activated by PI 3-kinase signaling, we evaluated whether formation of Ca2ϩ-dependent cell-cell adhesion in adherent PC3N cells could affect the activation state of Akt by assessing phosphorylation of Akt on Ser-473 using a phospho-specific antibody (Fig. 2A).
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