Chrysophanic acid reduces testosterone-induced benign prostatic hyperplasia in rats by suppressing 5α-reductase and extracellular signal-regulated kinase.

Gautam Sethi,Dong-Hyun Youn,Jongwook Kang,Yunu Jung,Jae-Young Um,Mi-Young Jeong,Kwang Seok Ahn,Jinbong Park,Hye-Lin Kim

doi:10.18632/oncotarget.13430

Gautam Sethi, Dong-Hyun Youn + Show 7 more

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https://doi.org/10.18632/oncotarget.13430

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Abstract

Benign prostatic hyperplasia (BPH) is one of the most common chronic diseases in male population, of which incidence increases gradually with age. In this study, we investigated the effect of chrysophanic acid (CA) on BPH. BPH was induced by a 4-week injection of testosterone propionate (TP). Four weeks of further injection with vehicle, TP, TP + CA, TP + finasteride was carried on. In the CA treatment group, the prostate weight was reduced and the TP-induced histological changes were restored as the normal control group. CA treatment suppressed the TP-elevated prostate specific antigen (PSA) expression. In addition, 5α-reductase, a crucial factor in BPH development, was suppressed to the normal level close to the control group by CA treatment. The elevated expressions of androgen receptor (AR), estrogen receptor α and steroid receptor coactivator 1 by TP administration were also inhibited in the CA group when compared to the TP-induced BPH group. Then we evaluated the changes in three major factors of the mitogen-activated protein kinase chain during prostatic hyperplasia; extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38). While ERK was elevated in the process of BPH, JNK and p38 was not changed. This up-regulated ERK was also reduced as normal by CA treatment. Further in vitro studies with RWPE-1 cells confirmed TP-induced proliferation and elevated AR, PSA and p-ERK were all reduced by CA treatment. Overall, these results suggest a potential pharmaceutical feature of CA in the treatment of BPH.

Highlights

Benign prostatic hyperplasia (BPH) is an extremely common disease in aging men, originally meaning hyperplasia of the prostate gland, an encapsulated accessory sex gland that surrounds the bladder neck and proximal urethra
We demonstrated the effects of chrysophanic acid (CA) on BPH in testosterone propionate (TP)-induced BPH rats by measuring the prostate tissue weight, examining the histological changes, and evaluating the major factors involved in the biology of BPH such as prostate specific antigen (PSA), 5AR, androgen receptor (AR), steroid receptor coactivator 1 (SRC1), estrogen receptor α (ERα), and mitogen-activated protein kinases (MAPKs)
There was no significant difference in body weights of rats whether they went through TP treatment or not, or treated by CA or finasteride (Fi), the well-known 5ARI (Table 1)

Summary

Introduction

Benign prostatic hyperplasia (BPH) is an extremely common disease in aging men, originally meaning hyperplasia of the prostate gland, an encapsulated accessory sex gland that surrounds the bladder neck and proximal urethra. Testosterone and DHT both bind to the same receptor, the AR, which results in increased transcription of androgen-dependent genes and stimulation of the protein synthesis [9]. AR has additional functions such as inducing the activation of kinase-signaling cascades or modulating the intracellular calcium levels [11], but in the biology of BPH, its role as a DNA-binding transcription factor which can regulate gene expression is the most important feature [12]. Expression of androgen regulated genes is affected by co-regulators that influence various functions of AR [13] These coregulators such as steroid receptor coactivator 1 (SRC1) modify the transcriptional activity of AR which could be related to BPH. The action of androgens in the prostate is mediated indirectly through autocrine and paracrine pathways

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