title: In search of the molecular mechanisms mediating the inhibitory effect of the GnRH antagonist degarelix on human prostate cell growth.
abstract: Degarelix is a gonadrotropin-releasing hormone (GnRH) receptor (GnRHR) antagonist used in patients with prostate cancer who need androgen deprivation therapy. GnRHRs have been found in extra-pituitary tissues, including prostate, which may be affected by the GnRH and GnRH analogues used in therapy. The direct effect of degarelix on human prostate cell growth was evaluated. Normal prostate myofibroblast WPMY-1 and epithelial WPE1-NA22 cells, benign prostatic hyperplasia (BPH)-1 cells, androgen-independent PC-3 and androgen-dependent LNCaP prostate cancer cells, as well as VCaP cells derived from a patient with castration-resistant prostate cancer were used. Discriminatory protein and lipid fingerprints of normal, hyperplastic, and cancer cells were generated by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The investigated cell lines express GNRHR1 and GNRHR2 and their endogenous ligands. Degarelix treatment reduced cell viability in all prostate cell lines tested, with the exception of the PC-3 cells; this can be attributed to increased apoptosis, as indicated by increased caspase 3/7, 8 and 9 levels. WPE1-NA22, BPH-1, LNCaP, and VCaP cell viability was not affected by treatment with the GnRH agonists leuprolide and goserelin. Using MALDI MS, we detected changes in m/z signals that were robust enough to create a complete discriminatory profile induced by degarelix. Transcriptomic analysis of BPH-1 cells provided a global map of genes affected by degarelix and indicated that the biological processes affected were related to cell growth, G-coupled receptors, the mitogen-activated protein kinase (MAPK) pathway, angiogenesis and cell adhesion. Taken together, these data demonstrate that (i) the GnRH antagonist degarelix exerts a direct effect on prostate cell growth through apoptosis; (ii) MALDI MS analysis provided a basis to fingerprint degarelix-treated prostate cells; and (iii) the clusters of genes affected by degarelix suggest that this compound, in addition to its known use in the treatment of prostate cancer, may be efficacious in BPH.
authors: The Research Institute of the McGill University Health Center, Montréal, Québec, Canada; Department of Medicine, McGill University, Montréal, Québec, Canada.
authors: Monica
authors: M
authors: Sakai
authors: The Research Institute of the McGill University Health Center, Montréal, Québec, Canada; Department of Medicine, McGill University, Montréal, Québec, Canada.
authors: Daniel B
authors: DB
authors: Martinez-Arguelles
authors: Department of Chemistry, University of Montreal, Montréal, Québec, Canada.
authors: Nathan H
authors: NH
authors: Patterson
authors: Department of Chemistry, University of Montreal, Montréal, Québec, Canada.
authors: Pierre
authors: P
authors: Chaurand
authors: The Research Institute of the McGill University Health Center, Montréal, Québec, Canada; Department of Medicine, McGill University, Montréal, Québec, Canada; Departments of Biochemistry, McGill University, Montréal, Québec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors: Vassilios
authors: V
authors: Papadopoulos
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D063990:Gene Ontology; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D017273:Goserelin / Q000494:pharmacology; D006801:Humans; D016729:Leuprolide / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D011467:Prostate / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D011966:Receptors, LHRH; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D017273:Goserelin; D007987:Gonadotropin-Releasing Hormone; D020169:Caspases; D016729:Leuprolide