Growth hormone‐releasing hormone antagonists reduce prostatic enlargement and inflammation in carrageenan‐induced chronic prostatitis

• Published in: The Prostate Vol. 78; no. 13; pp. 970 - 980
• Main Authors: Popovics, Petra, Cai, Renzhi, Sha, Wei, Rick, Ferenc G., Schally, Andrew V.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-09-2018
• Subjects: AKT protein; Autoimmune diseases; benign prostatic hyperplasia; Cytokines; Epidermal growth factor receptors; epithelial‐to‐mesenchymal transition; Etiology; growth factor; Growth factors; Growth hormone-releasing hormone; Growth hormones; Hyperplasia; Inflammation; Insulin-like growth factors; Mesenchyme; neuropeptide; NF-κB protein; Prostate; Prostatitis; Signal transduction; Stat3 protein; targeted therapy; Transforming growth factor-b1; growth factor; targeted therapy; neuropeptide; benign prostatic hyperplasia; epithelial-to-mesenchymal transition
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.23655

Background
Inflammation plays a key role in the etiology of benign prostatic hyperplasia (BPH) through multiple pathways involving the stimulation of proliferation by cytokines and growth factors as well as the induction of the focal occurrence of epithelial‐to‐mesenchymal transition (EMT). We have previously reported that GHRH acts as a prostatic growth factor in experimental BPH and in autoimmune prostatitis models and its blockade with GHRH antagonists offer therapeutic approaches for these conditions. Our current study was aimed at the investigation of the beneficial effects of GHRH antagonists in λ‐carrageenan‐induced chronic prostatitis and at probing the downstream molecular pathways that are implicated in GHRH signaling.
Methods
To demonstrate the complications triggered by recurrent/chronic prostatic inflammation in Sprague‐Dawley rats, 50 μL 3% carrageenan was injected into both ventral prostate lobes two times, 3 weeks apart. GHRH antagonist, MIA‐690, was administered 5 days after the second intraprostatic injection at 20 μg daily dose for 4 weeks. GHRH‐induced signaling events were identified in BPH‐1 and in primary prostate epithelial (PrEp) cells at 5, 15, 30, and 60 min with Western blot.
Results
Inflammation induced prostatic enlargement and increased the area of the stromal compartment whereas treatment with the GHRH antagonist significantly reduced these effects. This beneficial activity was consistent with a decrease in prostatic GHRH, inflammatory marker COX‐2, growth factor IGF‐1 and inflammatory and EMT marker TGF‐β1 protein levels and the expression of multiple genes related to EMT. In vitro, GHRH stimulated multiple pathways involved in inflammation and growth in both BPH‐1 and PrEp cells including NFκB p65, AKT, ERK1/2, EGFR, STAT3 and increased the levels of TGF‐β1 and Snail/Slug. Most interestingly, GHRH also stimulated the transactivation of the IGF receptor.
Conclusions
The study demonstrates that GHRH antagonists could be beneficial for the treatment of prostatic inflammation and BPH in part by inhibiting the growth‐promoting and inflammatory effects of locally produced GHRH.