Broad and diverse roles of sphingosine-1-phosphate/sphingosine-1-phosphate receptors in the prostate

Benign prostatic hyperplasia (BPH) is a common condition in aging males, but its underlying pathogenesis remains unclear. Sphingosine-1-phosphate (S1P) and its receptors (S1PRs) play important roles in various diseases, while less studied in prostate. Current study attempts to clarify the expression and functional activities of S1P/S1PRs in the prostate. We discovered that S1P/S1PRs were richly expressed in the prostate, with S1PR1/2/3 localized in the epithelial/stromal compartments, while S1PR4/5 were less expressed. <i>In vitro</i>, S1P/S1PR1/S1PR3 promoted cell proliferation via AKT and ERK1/2 pathways, S1P/S1PR2/S1PR3 enhanced contraction of WPMY-1 cells and human prostate via RhoA/ROCK pathway, while S1P/S1PR1/S1PR2/S1PR3 alleviated the inflammation response via STAT3 pathway. <i>In vivo</i>, S1P and S1PR1/3 agonists (SEW2871, CYM5541) led to prostate enlargement in rats, while S1PR1/3 antagonists (W-146, TY-52156) suppressed testosterone-induced BPH. Overall, this study suggests that S1P/S1PRs play a critical role in the development of BPH and may be a promising therapeutic target for BPH treatment.