This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Gap junctions are conglomerations of cell-cell channels that are formed by a family of proteins, called connexins, which are designated according to molecular mass. They permit the direct passage of small molecules between adjoining cells. Our studies have shown that in invasive prostate tumors connexin32 and connexin43 remain intracellular whereas in well differentiated prostate tumors both connexins are assembled into gap junctions. Moreover, forced expression of both connexins in prostate cancer cells induces differentiation and inhibits growth in vitro and in vivo. Our studies have also shown that expression of anti-metastatic E-cadherin facilitates gap junction assembly, whereas expression of pro-invasive N-cadherin disrupts assembly. Our central hypothesis is that bidirectional signaling between cadherins and connexins is required to maintain the polarized and the differentiated state of epithelial cells and that gap junction assembly is the downstream target of signaling initiated by cadherins, with E-cadherin facilitating the assembly and N-cadherin promoting the disassembly. The proposed studies in aim 1 will determine how E-cadherin mediated cell-cell adhesion controls the assembly of connexins into gap junctions in prostate cancer cells. The hypothesis to be tested is that cadherin mediated cell-cell adhesion induces a signaling cascade, which modulates gap junction assembly. Wild type and extracellular domain deleted cadherins that are unable to induce cell-cell adhesion will be used. The proposed studies in aim 2 will determine the molecular mechanisms by which E-cadherin and N-cadherin modulate gap junction assembly differentially.
This aim tests the hypothesis that E-cadherin facilitates gap junction assembly by preventing the endocytosis of connexins whereas N-cadherin promotes disassembly by inducing endocytosis. E-cadherin and N-cadherin will be knocked down in various prostate cancer cell lines in which connexins are either assembled into gap junctions or remain intracellular. Alternatively, wild type N-cadherin, and its chimeras that modulate cell motility differentially, will be expressed in Ecadherin expressing prostate cancer cell lines. These studies will enhance our understanding about the role of cadherins and connexins in the pathogenesis of prostate cancer.
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