title: Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells.
abstract: The etiology of benign prostatic hyperplasia (BPH) is multifactorial, and chronic inflammation plays a pivotal role in its pathogenesis. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that has been shown to act as paracrine/autocrine factor in various malignancies including prostate cancer. GHRH and its receptors are expressed in experimental models of BPH, in which antagonists of GHRH suppressed the levels of proinflammatory cytokines and altered the expression of genes related to epithelial-to-mesenchymal transition (EMT). We investigated the effects of GHRH antagonist on prostatic enlargement induced by inflammation. Autoimmune prostatitis in Balb/C mice was induced by a homogenate of reproductive tissues of male rats. During the 8-wk induction of chronic prostatitis, we detected a progressive increase in prostatic volume reaching 92% at week 8 compared with control (P < 0.001). Daily treatment for 1 mo with GHRH antagonist MIA-690 caused a 30% reduction in prostate volume (P < 0.05). Conditioned medium derived from macrophages increased the average volume of spheres by 82.7% (P < 0.001) and elevated the expression of mRNA for N-cadherin, Snail, and GHRH GHRH antagonist reduced the average volume of spheres stimulated by inflammation by 75.5% (P < 0.05), and TGF-β2 by 91.8% (P < 0.01). The proliferation of primary epithelial cells stimulated by IL-17A or TGF-β2 was also inhibited by 124.1% and 69.9%, respectively. GHRH stimulated the growth of BPH-1 and primary prostate spheres. This study provides evidence that GHRH plays important roles in prostatic inflammation and EMT and suggests the merit of further investigation to elucidate the effects of GHRH antagonists in prostatitis and BPH.
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125; petra.popovics@gmail.com andrew.schally@va.gov.|Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Petra
authors.initials: P
authors.lastname: Popovics
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125; petra.popovics@gmail.com andrew.schally@va.gov.|Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL 33136.|Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136.|Division of Hematology/Oncology, Miller School of Medicine, University of Miami, Miami, FL 33136.|Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136.|Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125.|Institute for Neuro Immune Medicine, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314.
authors.forename: Luis
authors.initials: L
authors.lastname: Salgueiro
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125.|Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kovacs
authors.affiliation: Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL 33125.|Department of Urology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33174.
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011472:Prostatitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051381:Rats; D053781:Transforming Growth Factor beta2 / Q000494:pharmacology
chemical_list: C411623:JV 1-38; D053781:Transforming Growth Factor beta2; D013007:Growth Hormone-Releasing Hormone
keywords: chronic prostatic inflammation; experimental autoimmune prostatitis; neuropeptide; prostatic hyperplasia; targeted therapy