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Connexins and Cadherin Cross-talk in the Pathogenesis of Prostate Cancer
Annual rept. 1 Sep 2013-31 Aug 2014
NEBRASKA UNIV MEDICAL CENTER OMAHA
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Gap junctions are conglomerations of cell-cell channels that are formed by a family of distinct proteins, called connexins. Cell-cell adhesion is mediated by cadherins, which assemble into adherens junctions. Our central hypothesis is that bidirectional signaling between cadherins and connexins is required for the assembly of gap junctions. We have postulated that connexins are the downstream targets of the signaling initiated by the classical cadherins, with epithelial-cadherin facilitating assembly and neuronal cadherin inhibiting the assembly. We have found that expression of a cell-cell adhesion deficient mutant of E-cadherin, in which tryptophan at position 156 in the first extracellular domain is replaced with alanine, acts in a dominant-negative manner when expressed in E-cadherin-expressing human prostate cancer cell line, LNCaP, and abolishes cell-cell adhesion as well as alters their morphology. Expression of alpha-catenin in metastatic prostate cancer cell line, PC3M, in which this gene is deleted and in which connexins are not assembled into gap junctions, induces mesenchymal to epithelial transformation and partially restores gap junction assembly. These findings highlight the importance of connexins and cadherins in the pathogenesis of prostate cancer.
APPROVED FOR PUBLIC RELEASE