PROSTATE GROWTH REGULATION BY ADRENERGIC RECEPTORS

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Benign prostatic hyperplasia (BPH) is the most common neoplastic condition affecting males in the United States. The long term objective of the proposal is to understand mechanism underlying the development of BPH. Within this context, the current proposal is designed to test the overall hypothesis that catecholamines initiate prostate stromal growth. Current data suggests BPH is initially a stomal disease with the initiating event being proliferation of prostatic fibroblasts and/or smooth muscle cells, although individual factor(s) responsible for this process remain unknown. Catecholamines have recently been shown to induce mitogenesis in a number of cell types (including rat prostate stromal cells), and evidence from cultured vascular and cardiac cells implicates catecholamines in both hypertrophic and hyperplastic responses. Furthermore, activation of G-protein coupled receptors (such as adrenergic receptors) can convergently activate a common mitogenic pathway with tyrosine kinase receptors; this pathway involves activation of p21ras proteins and mitogen activated protein (MAP) kinases which then initiate a series of events involved in cell growth and division. Catecholamines have also been shown to regulate peptide growth factor production in various cells, representing another method whereby catecholamines could indirectly modulate prostate growth through an autocrine or paracrine mechanism. In the current proposal, the first specific aim investigates the potential role of norepinephrine (NE) as a growth factor involved in initiating prostate stromal hyperplasia in a rodent model using a biodegradable NE releasing pellet. A parallel evaluation of the mitogenic effects of NE on cultured human prostate stromal cells will be performed on both primary and stable prostate stromal cell lines. The second specific aim examines in vitro effects of NE on growth factor production, using a variety of techniques including RNase protection assays and western blot analysis. The third hypothesis examines mitogenic pathways in prostate stromal cells by investigating ras and MAP kinase activation in response to NE stimulation of cultured prostate stromal cells; adrenergic receptors involved in the activation of this pathway will be determined using subtype selective antagonists. Subsequent experiments will define intracellular pathways involved in the mitogenic response by transiently expressing peptides encoding for Galpha and Gbetagamma subunits, which have been shown in previous experiments to uncouple G-protein coupled receptor mitogenic pathways.