Simvastatin Improves Benign Prostatic Hyperplasia: Role of Peroxisome-Proliferator-Activated Receptor-gamma and Classic WNT/beta-Catenin Pathway

Benign prostatic hyperplasia (BPH) is a common disease in elderly men with an uncertain etiology and mechanistic basis. Metabolic syndrome (MetS) is also a very common illness and is closely related to BPH. Simvastatin (SV) is one of the widely used statins for MetS. Peroxisome-proliferator-activated receptor gamma (PPAR gamma), crosstalking with the WNT/beta-catenin pathway, plays important roles in MetS. Our current study aimed to examine SV-PPAR gamma-WNT/beta-catenin signaling in the development of BPH. Human prostate tissues and cell lines plus a BPH rat model were utilized. Immunohistochemical, immunofluorescence, hematoxylin and eosin (H & E) and Masson's trichrome staining, construction of a tissue microarray (TMA), ELISA, CCK-8 assay, qRT-PCR, flow cytometry, and Western blotting were also performed. PPAR gamma was expressed in both prostate stroma and epithelial compartments and downregulated in BPH tissues. Furthermore, SV dose-dependently triggered cell apoptosis and cell cycle arrest at the G0/G1 phase and attenuated tissue fibrosis and the epithelial-mesenchymal transition (EMT) process both in vitro and in vivo. SV also upregulated the PPAR gamma pathway, whose antagonist could reverse SV produced in the aforementioned biological process. Additionally, crosstalk between PPAR gamma and WNT/beta-catenin signaling was demonstrated. Finally, correlation analysis with our TMA containing 104 BPH specimens showed that PPAR gamma was negatively related with prostate volume (PV) and free prostate-specific antigen (fPSA) and positively correlated with maximum urinary flow rate (Qmax). WNT-1 and beta-catenin were positively related with International Prostate Symptom Score (IPSS) and nocturia, respectively. Our novel data demonstrate that SV could modulate cell proliferation, apoptosis, tissue fibrosis, and the EMT process in the prostate through crosstalk between PPAR gamma and WNT/beta-catenin pathways.