Smoothened inhibition leads to decreased cell proliferation and suppressed tissue fibrosis in the development of benign prostatic hyperplasia

Abstract

Benign prostatic hyperplasia (BPH) is a common disease in aging males. It has been proven that the Hedgehog (HH) is implied as an effective and fundamental regulatory growth factor signal for organogenesis, homeostasis, and regeneration. Smoothened (SMO), as the major control point of HH signals, activates aberrantly in most human solid tumors. However, the specific function of SMO and its downstream glioma-associated oncogene (GLI) family in BPH has not been well understood. Here, we first revealed that the SMO cascade was upregulated in BPH tissues and was localized in both the stromal and the epithelium compartments of human prostate tissues. Cyclopamine, as a specific SMO inhibitor, was incubated with BPH-1 and WPMY-1, and intraperitoneally injected into a BPH rat model established by castration with testosterone supplementation. SMO inhibition could induce cell apoptosis, cell cycle arrest at the G0/G1 phase, and a reduction of tissue fibrosis markers, both in vitro and in vivo. Finally, a tissue microarray, containing 104 BPH specimens, was constructed to analyze the correlations between the expression of SMO cascade and clinical parameters. The GLI2 was correlated positively with nocturia and negatively with fPSA. The GLI3 was in a positive relationship with International Prostate Symptom Score and nocturia. In conclusion, our study suggested that SMO cascade could play important roles in the development of BPH and it might be rediscovered as a promising therapeutic target for BPH.

The Role of Heat Shock Protein 70 Subfamily in the Hyperplastic Prostate: From Molecular Mechanisms to Therapeutic Opportunities

“…Cordon-Cardo et al firstly reported that p27KIP1, a negative regulator of the cell cycle, decreased within hyperplastic prostate tissues, while lack of the p27KIP1 gene increased the proliferative activity of prostatic cells [24]. Our recently published evidence also suggested that bone morphogenetic protein 5 (BMP5) and Smoothened (SMO), alongside the downstream glioma-associated oncogene (GLI) family, stimulated cellular proliferation of BPH-1 and WPMY-1 cells by promoting cell cycle progression [25,26]. Apoptosis has been known as one of the programmed cell death mechanisms.…”

Cinnamomum cassia and Rosa laevigata Mixture Improves Benign Prostatic Hyperplasia in Rats by Regulating Androgen Receptor Signaling and Apoptosis

“…The disruption of the molecular mechanisms in these two processes may lead to BPH [ 48 ]. Although the mechanism of BPH is not fully understood, previous studies reported that inducing apoptosis and the inhibition of cell proliferation contributes to the treatment of BPH [ 49 , 50 ]. A decrease in apoptotic activity plays an important role in the BPH pathogenesis [ 51 ].…”

Glutathione Peroxidase 3 induced mitochondria-mediated apoptosis via AMPK /ERK1/2 pathway and resisted autophagy-related ferroptosis via AMPK/mTOR pathway in hyperplastic prostate

“…Cell lines obtained and cultured, CCK-8 assay, total RNA extraction, RNA reverse transcription, qRT-PCR analysis, Western blot analysis, hematoxylin and eosin (H&E) staining and masson’s trichrome staining analysis were performed as we previously described [ 35 , 36 ]. Primer sequences were summarized in Additional file 1 : Table S1.…”