The focus in this application is on the switch in cadherin expression during prostate cancer progression to examine the intracellular signaling events that cause tumor cells to become metastatic. Important determinants for metastasis are not only the detachment of prostate carcinoma cells from the primary tumor by down regulation of E-cadherin, but also their ability to survive in different microenvironments. While the mechanisms by which stroma supports prostate cancer progression are unknown, one factor that may contribute to the enhancement of carcinoma cell survival by stromal cells maybe cell-cell adhesion. We have shown that the more invasive human prostate carcinoma cell lines have down-regulated E-cadherin and gained expression of N-cadherin. Carcinoma cells can form stable adherens junction complexes with N-cadherin on prostate-derived stromal fibroblasts. Our findings indicate that homophilic N-cadherin adhesion on adjacent prostate carcinoma cells is able to transduce an outside-in cell survival signal through activation of PI 3-kinase, and down-stream activation of serine/threonine kinase AKT/PKB, which can phosphorylate Bad and CREB. This proposal examines the hypothesis that expression of non-epithelial cadherin subtypes by prostate carcinomas contributes to the molecular events during invasion, which increase tumor cell survival and eventually lead to metastasis. To explore this hypothesis we will focus on the regulation of two critical cadherin subtypes, E-cadherin and N-cadherin, and their co-expression in the progression of prostate carcinomas.
Specific aims are:
Aim 1 : Determine the mechanism of N-cadherin mediated adherens junctions signaling in prostate carcinoma cell survival pathways.
Aim 2 : Extend characterization of Bcl-2 regulation by the homophilic adhesion of N-cadherin.
Aim 3 : Investigate the molecular basis for N-cadherin mediated enhancement of the migratory phenotype of E-cadherin expressing prostate carcinomas.
Aim 4 : Determine the consequences of N-cadherin expression in epithelium of transgenic mice by prostate-directed over expression. Understanding the functional role of these changes in cadherin family of cell-cell adhesion molecules that lead to metastasis, would provide a potential prognostic indicator to identify individuals who are more likely to develop aggressive prostate cancer.
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