gastrin-releasing-peptide and Prostatic-Hyperplasia

In prostate cancer (PCa), neuroendocrine cells (NE) have been associated with the progression of the disease due to the secretion of neuropeptides that are capable of diffusing and influence surrounding cells. The GABAergic system is enriched in NE-like cells, and contributes to PCa progression. Additionally, γ-aminobutyric acid (GABA) stimulates the secretion of gastrin-releasing peptide (GRP) in peripheral organs. For the first time, in this study we show the role of GABA and GABA

Topics: Adenocarcinoma; Aged; Cohort Studies; Disease Progression; GABA Agents; gamma-Aminobutyric Acid; Gastrin-Releasing Peptide; Humans; Male; Middle Aged; Neuroendocrine Cells; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Androgen; RNA, Small Interfering; Tumor Cells, Cultured

Topics: Animals; Bombesin; Cell Size; Gastrin-Releasing Peptide; Humans; Male; Peptide Fragments; Prostate; Prostatic Hyperplasia

Topics: Animals; Bombesin; Cell Size; Gastrin-Releasing Peptide; Humans; Male; Peptide Fragments; Prostate; Prostatic Hyperplasia

Gastrin releasing-peptide (GRP) is a potent growth factor in many malignancies. Benign prostatic hyperplasia (BPH) is a progressive age-related proliferation of glandular and stromal tissues; various growth factors and inflammatory processes are involved in its pathogenesis. We have demonstrated that potent antagonists of GRP inhibit growth of experimental human tumors including prostate cancer, but their effect on models of BPH has not been studied. Here, we evaluated the effects of GRP antagonist RC-3940-II on viability and cell volume of BPH-1 human prostate epithelial cells and WPMY-1 prostate stromal cells in vitro, and in testosterone-induced BPH in Wistar rats in vivo. RC-3940-II inhibited the proliferation of BPH-1 and WPMY-1 cells in a dose-dependent manner and reduced prostatic cell volume in vitro. Shrinkage of prostates was observed after 6 wk of treatment with RC-3940-II: a 15.9% decline with 25 μg/d; and a 18.4% reduction with 50 μg/d (P < 0.05 for all). Significant reduction in levels of proliferating cell nuclear antigen, NF-κβ/p50, cyclooxygenase-2, and androgen receptor was also seen. Analysis of transcript levels of genes related to growth, inflammatory processes, and signal transduction showed significant changes in the expression of more than 90 genes (P < 0.05). In conclusion, GRP antagonists reduce volume of human prostatic cells and lower prostate weight in experimental BPH through direct inhibitory effects on prostatic GRP receptors. GRP antagonists should be considered for further development as therapy for BPH.

Topics: Analysis of Variance; Animals; Apoptosis; Blotting, Western; Bombesin; Cell Line; Cell Proliferation; Cell Size; Cyclooxygenase 2; Dose-Response Relationship, Drug; Gastrin-Releasing Peptide; Gene Expression Profiling; Humans; Male; NF-kappa B; Peptide Fragments; Proliferating Cell Nuclear Antigen; Prostate; Prostatic Hyperplasia; Rats; Real-Time Polymerase Chain Reaction; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; Testosterone; Tetrazolium Salts; Thiazoles

Bombesin-like peptides (BLPs), which have been implicated in the regulation of growth of prostatic carcinoma cells, are a product of neuroendocrine cells frequently found in prostate tissue and are postulated to play a role in the initiation or progression of prostatic carcinoma. In this report, we examined the expression, in human prostate tissue, of mRNA encoding the 3 known receptors that respond to BLPs in humans, i.e., gastrin-releasing peptide (GRP) receptor, neuromedin B (NMB) receptor and bombesin receptor subtype 3 (BRS-3). Competitive rt-PCR experiments demonstrated the widespread but variable expression of GRP receptor mRNA in fresh-frozen specimens of prostatic carcinoma (12 cases) and benign prostatic hypertrophy (6 cases). NMB receptor mRNA expression was also widespread, but its level was less variable than GRP receptor message. In contrast, we could not detect BRS-3 mRNA in most tissue samples by rt-PCR. To address which cells in the prostate express the GRP receptor, we used in situ hybridization methods to stain selectively GRP receptor mRNA. GRP receptor mRNA was expressed predominantly in the luminal and basal epithelial cells in both histologically normal and cancerous glands within sections of normal (3 cases) and diseased (37 cases) tissue. GRP receptor mRNA staining in cancerous tissue ranged widely from very intense to not detectable (about 30% of the cases), while normal tissue consistently displayed a low level of message staining. Taken together, our results demonstrate expression of the GRP receptor in a high percentage of basal and/or luminal epithelial cells of normal and diseased prostate tissues.

Topics: Gastrin-Releasing Peptide; Humans; In Situ Hybridization; Male; Neurokinin B; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Radioligand Assay; Receptors, Bombesin; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured