The cell-cell channels in gap junctions, formed of proteins called connexins (Cxs), link the cytoplasmic interiors of adjoining cells and provide an intercellular pathway for the diffusion of growth-regulatory molecules. We have observed alterations in the expression and function of Cx genes between prostate carcinoma and normal prostate cells in vitro. We plan now to delineate these differences and test the hypothesis that a homeostatic mechanism mediated by gap-junctional communication controls the growth, differentiation, and apoptotic death of prostatic epithelial cells and may have a role in preventing the progression of prostate cancer from latency to clinical manifestation. In the first aim, we will explore the cellular and physiological mechanisms by which formation of gap junctions in malignant prostate epithelial cells inhibits growth and induces differentiation and apoptosis through delineation of effects resulting from the diffusion of putative growth- regulatory molecules and the cooperation/redundancy among various kinds of cell junctions, specifically those mediated by E- cadherin. This will be tested by inducing the formation of gap junctions composed of normal Cxs that will allow the passage of putative growth-regulatory molecules and those of mutant Cxs that will impede their passage. In the second aim, we hypothesize that the expression of Cxs and their assembly into gap junctions are regulated by the modulators of prostatic growth and cancer, such as growth factors and the androgens. This hypothesis will be tested by studying the effects of growth factors, known to be produced during the progression of prostate cancer, on the assembly and function of gap junctions composed of Cx32 and Cx43. In the third aim, we hypothesize that signal transduction through cell-matrix adhesion controls the assembly of Cxs into gap junctions, or vice versa, and thereby governs the growth, differentiation, and apoptosis in human prostate cancer cells. This hypothesis will be tested by inducing the formation of gap junctions in human prostate cancer cells, which express Cxs but fail to form gap junctions, by plating them on various components of extracellular matrix and studying the effects on growth, differentiation, and apoptosis. Such experiments should enhance our knowledge about the pathobiology of prostate cancer.
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