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
View: Text | PDF
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

×

Figure 2

Prostate cell DNA damage response triggers npGH expression, further enhancing prostate DNA damage accumulation.

Options: View larger image (or click on image) Download as PowerPoint
Prostate cell DNA damage response triggers npGH expression, further enha...
(A–C) Western blots in (A) HPrEC line 1, (B) HPrEC line 2, and (C) NAFs treated with indicated doses of etoposide for 24 hours. (D–F) Western blots of (D) HPrEC line 1, (E) HPrEC line 2, and (F) PNT2 treated with indicated doses of GH and analyzed 24 hours later. (G and H) Western blots in (G) HPrEC line 1 and (H) PNT2 cocultured with lentiGH- or lentiV-infected NAFs for 24 hours. (I) Western blots in PNT2 infected with lentivirus expressing scramble shRNA (shControl) or GHR shRNA (shGHR) and analyzed 4 days later. (J) PNT2 treated with indicated doses of BM001 and analyzed 6 hours later. (K) Western blots in lentiGH- or lentiV-infected PNT2 and analyzed 4 weeks later. (L–N) Comet assay quantifying DNA damage in (L) HPrEC line 1, (M) HPrEC line 2, and (N) PNT2 treated with indicated doses of GH for 24 hours compared with control. (O and P) Comet assay quantifying DNA damage in (O) PNT2 and (P) lentiGH- or lentiV-infected NAFs and analyzed 4 weeks later. (Q) Western blot in prostate tissue derived from 24-month-old WT or GHR–/– mice. For A–K, representative blots from at least 3–4 independent experiments are shown. For A–K, ImageJ quantification of Western blots is depicted in Supplemental Figure 2, A–F, H–K, and M. For L–Q, 200–400 nuclei were analyzed in 3 separate experiments, each represented by 1 dot. Results shown are mean ± SEM. Results are shown as percentage of control, but statistical testing was performed on raw numbers. *P < 0.05, **P < 0.01 versus control by 2-way ANOVA followed by Tukey’s post hoc test to adjust for multiple comparisons (L–N) or 2-tailed Student’s t test (O and P). For Q, ImageJ quantifications of Western blots are depicted in Supplemental Figure 2P.