The treatment effects of flaxseed-derived secoisolariciresinol diglycoside and its metabolite enterolactone on benign prostatic hyperplasia involve the G protein-coupled estrogen receptor 1.

Key Findings

Benign prostatic hyperplasia (BPH) is a progressive age-related pathologic proliferation of prostatic glandular and stromal tissues. In this study, in vivo data showed that SDG treatment activated the G protein-coupled estrogen receptor 1 (GPER), a protein which binds to and is activated by the female sex hormone estradiol. This activation inhibited the enlargement of BPH. The results provide new evidence that lignans suppress BPH both in vitro and in vivo. The mammalian lignan of enterolactone (ENL) inhibited WPMY-1 cell growth (a cell line that is used to study carcinogenesis, tumor progression, prevention and treatment of prostate cancer and benign prostatic hyperplasia) associated by the induction of G0/G1 cell cycle arrest. ENL-induced cell cycle arrest may be mediated by the activation different pathways.

ABSTRACT

Secoisolariciresinol diglucoside (SDG), a lignan extracted from flaxseed, has been shown to suppress benign prostatic hyperplasia (BPH). However, little is known about the mechanistic basis for its anti-BPH activity. The present study showed that enterolactone (ENL), the mammalian metabolite of SDG, shared the similar binding site of G1 on a new type of membranous estrogen receptor, G-protein-coupled estrogen eceptor 1 (GPER), by docking simulations method. ENL and G1 (the specific agonist of GPER) inhibited the proliferation of human prostate stromal cell line WPMY-1 as shown by MTT assay and arrested cell cycle at the G0/G1 phase, which was displayed by propidium iodide staining following flow cytometer examination. Silencing GPER by short interfering RNA attenuated the inhibitory effect of ENL on WPMY-1 cells. The therapeutic potential of SDG in the treatment of BPH was confirmed in a testosterone propionate-induced BPH rat model. SDG significantly reduced the enlargement of the rat prostate and the number of papillary projections of prostatic alveolus and thickness of the pseudostratified epithelial and stromal cells when comparing with the model group. Mechanistic studies showed that SDG and ENL increased the expression of GPER both in vitro and in vivo. Furthermore, ENL-induced cell cycle arrest may be mediated by the activation of GPER/ERK pathway and subsequent upregulation of p53 and p21 and downregulation of cyclin D1. This work, in tandem with previous studies, will enhance our knowledge regarding the mechanism(s) of dietary phytochemicals on BPH prevention and ultimately expand the scope of adopting alternative approaches in BPH treatment.