Hormonelle Regulation der Enzymaktivität, Proteinexpression und Bedeutung der Neutralen Endopeptidase in Zelllinien der benignen Prostatahyperplasie und des Prostatakarzinoms

In summary, our results demonstrate the expression and activity of NEP in the plasma membrane of prostatic stromal cells derived from human BPH-tissue, with the membrane-bound enzyme showing an approximately 25% lower activity relative to PC-cells (LNCaP). As described for epithelial cells of the prostate, the major function of NEP in the stroma might be the degradation of neuropeptides which are synthesized by neuroendocrine cells located in the prostatic epithelium, and might be secreted not only from the apical but also from the basal pole of the cells. Alternatively, neuropeptides in the prostatic stroma might originate from nerve terminals found in the stroma of the prostate. Some authors have reported a decrease in neuroendocrine cells and their products in BPH. They suggest that neuropeptides are involved in controlling cell proliferation through a paracrine hormonal mechanism and may be involved in the pathogenesis of BPH and prostate cancer. Moreover, the growth of hyperplastic prostate tissue is related to neuroendocrine cell activity and neuropeptides influence the contractile responses of the stroma cells. Neuropeptide degrading NEP also plays an important role in the transition from hormonally regulated androgen-dependent prostate cancer to androgen independent PC and has a tumor-suppressive effect on epithelial prostate cancer cells. Therefore, locally elevated concentrations of proinflammatory, mitogenic neuropeptides might arise. These peptides may in turn switch on signal transduction events responsible for an altered tissue composition observed in pathological processes such as PC and BPH. To address the influence of substrate induced regulatory processes on NEP expression, NEP activity and cell proliferation, we investigated the effects of the NEP substrates bombesin, substance P, Interleukin-1ß and neuroendocrine cell derived conditioned media on proliferation and activity of NEP. In the study presented, substance P downregulated NEP expression and the enzymatic activity on LNCaP cells. A minor downregulation of NEP activity on LNCaP cells was also induced by CRL-1803 conditioned media. Furthermore, CRL-1803 conditioned media were to some extent mitogenic to LNCaP cells. With the exception of an upregulation of proliferation following interleukin-1ß and procalcitonin application, only a basal regulation NEP activity and proliferation was observed for the stromal cells (hPCPs) after incubation with bombesin, substance P, IL-1ß and CRL-1803 conditioned media. This relative insensitivity of hPCPs cells to external stimuli has also been found previously in experiments performed with androgen, estrogen and flutamide and might be addressed to the lack of epithelial cells in the cultures of stromal cells. Comprehensive studies have to be performed to gain a deeper insight into the function of neuropeptides in the stromal compartment of the human prostate and to elucidate the regulation of NEP-activity in the prostatic stroma.