Local growth hormone promotes benign prostatic hyperplasia
Masaki Ryuzaki, Svetlana Zonis, Neil A. Bhowmick, Sandrine Billet, Saravana Kumar Kailasam Mani, Stephen J. Freedland, Hyung L. Kim, Vera Chesnokova, Shlomo Melmed
Masaki Ryuzaki, Svetlana Zonis, Neil A. Bhowmick, Sandrine Billet, Saravana Kumar Kailasam Mani, Stephen J. Freedland, Hyung L. Kim, Vera Chesnokova, Shlomo Melmed
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Research Article Aging Endocrinology

Local growth hormone promotes benign prostatic hyperplasia

Abstract

Locally produced nonpituitary growth hormone (npGH) promotes DNA damage accumulation and epithelial-mesenchymal transition (EMT) in aging human colon epithelium. GH receptor (GHR) and npGH are expressed in normal human prostate, and benign prostatic hyperplasia (BPH) prevalence increases with age. We hypothesized that local prostate GH action may promote EMT and contribute to BPH pathogenesis. We show here that the number of patients expressing npGH increases more than 10-fold after age 60, concordant with increased γH2AX, a marker of DNA damage, and EMT activation. GH-treated human primary prostate epithelial cells, normal prostate cells, and primary cell cultures derived from resected BPH specimens exhibited enhanced DNA damage and activated EMT, with induced TWIST2, suppressed E-cadherin, and increased Ki67, cell motility, and proliferation. In mice, prostate tissue adjacent to allografted GH-expressing fibroblasts showed increased γH2AX, TWIST2, and Ki67, along with morphological changes consistent with BPH. While GH and GH-induced IGF-1 both activated EMT, GH triggered DNA damage independently of IGF-1. These results elucidate what we believe to be a novel role for local npGH in aging prostate tissue, whereby npGH increases DNA damage and promotes EMT to enable a microenvironment favoring BPH development. Prostate GHR signaling may be an attractive therapeutic target for BPH.

Authors

Masaki Ryuzaki, Svetlana Zonis, Neil A. Bhowmick, Sandrine Billet, Saravana Kumar Kailasam Mani, Stephen J. Freedland, Hyung L. Kim, Vera Chesnokova, Shlomo Melmed

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Figure 5

IGF-1 induces EMT and proliferation, but attenuates DNA damage.

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IGF-1 induces EMT and proliferation, but attenuates DNA damage. (A and B...
(A and B) IGF-1 expression in prostate tissue derived from 4- to 6-month-old and 24-month-old WT male mice. (A) Western blot. (B) ImageJ quantification of expression normalized to loading controls. Average measurements of four 4- to 6-month-old and five 24-month-old mice are shown. Each dot represents sample analysis derived from an individual animal. Results are shown as mean ± SEM for each group. Data are graphed as percentage of control, but statistical testing was performed on raw numbers. Differences were assessed with 2-tailed Student’s t-test. (C and D) Western blots of protein expression in PNT2 cells treated with indicated doses of (C) IGF-1 or (D) IGF-1R inhibitor PPP and analyzed 24 hours later. tIGF-1R, total IGF-1 receptor; pIGF-1R, phosphorylated IGF-1R. (E) Western blot of protein expression in PNT2 cells treated with 50 nM PPP, 100 ng/mL GH, or both. (F) Western blot of protein expression in PNT2 cells infected with lentiGH or lentiV, treated with 50 nM PPP after 4 weeks and analyzed 24 hours later. (G and H) Comet assay in PNT2 cells treated with indicated doses of (G) IGF-1 or (H) PPP, GH, or both for 24 hours. Results shown are mean ± SEM. Each dot in G and H represents a single experiment in which 300–400 nuclei were analyzed. Results are shown as percentage of control, but statistical testing was performed on raw numbers. Results were analyzed by 2-way ANOVA followed by Tukey’s multiple-comparison test. *P < 0.05, **P < 0.01 versus control. For C–F, representative blots of at least 3 experiments are shown. ImageJ quantification of protein expression is shown in Supplemental Figure 5, S–V.