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 4

Autocrine/paracrine GH induces prostate EMT and proliferation.

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Autocrine/paracrine GH induces prostate EMT and proliferation. (A–E) Wes...
(A–E) Western blots of EMT marker expression in (A) PNT2 infected with lentiGH or lentiV and analyzed 4 weeks later, (B) HPrEC line 1 or (C) PNT2 cocultured for 24 hours with NAFs infected with lentiGH or lentiV; (D) PNT2 infected with lentivirus expressing control shRNA (shControl) or GHR shRNA (shGHR) and collected after 4 days; and (E) PNT2 treated with indicated doses of BM001 and analyzed 6 hours later. Representative blots from at least 3 independent experiments are shown. (F) Western blot of EMT marker expression in prostate tissue samples derived from 24-month-old WT (n = 5) and GHR–/– (n = 6) mice. For A–F, ImageJ quantification of Western blots is depicted in Supplemental Figure 4, A–E, and G. For B, the Western blot membrane from Figure 2G was stripped and re-probed for Ki67; the GAPDH loading control is the same. (G-I) Migration and (J-L) invasion of (G and J) PNT2 cells infected with lentiGH and lentiV and (H and K) HPrEC or (I and L) PNT2 cells co-cultured with lentiGH- or lentiV-infected NAF. Migrated or invaded cells were stained with crystal violet, imaged (magnification, ×100), and cells counted. Results shown are mean ± SEM/field. Each dot represents results of 2–3 separate experiments in duplicate or triplicate. Results are shown as percentage of control, but statistical testing was performed on raw numbers. Results were analyzed by 2-tailed Student’s t test. *P < 0.05, **P < 0.01 versus control.