BPH 10. Androgen peceptor for induction of proliferative responses and EMT in BPH cells by macrophage

Early studies suggested macrophage might play roles in Inflammationassociated benign prostatic hyperplasia (BPH) development, yet the underlying mechanism remains unclear. Here we first showed that CD68⁺ macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with human prostate epithelial (BPH-1) and macrophage cell lines (THP-1) to study the potential impacts of infiltrating macrophages in the BPH development. We found coculture BPH-1 cells with THP-1 cells would promote migration of THP-1 cells (to BPH-1 cells). In a three-dimensional (3D) culture system, the sphere diameter of BPH-1 cells was significantly increased during co-culture with THP-1 cells. Mechanism dissection suggested that expression levels of epithelialmesenchymal transition (EMT) markers, N-Cadherin, Snail, and TGF-β2 were increased, and administration of anti-TGF-β2 neutralizing antibody during co-culture led to suppress the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found modulation of AR in BPH-1 cells significantly increase THP-1 cell migration and expression levels of EMT markers, suggesting that AR might play a key role in promoting macrophage-mediated EMT that led to influence the BPH development and progression. Targeting AR via an AR degradation enhancer ASC-J9* led to suppress macrophagesmediated EMT and cell growth of BPH cells. Together, these results provided the first evidence to demonstrate that prostate epithelial AR function is important for macrophages-mediated EMT and proliferation of BPH-1 cells, which represents a previously unrecognized role of AR in the crosstalk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic approach to battle BPH via targeting AR and AR-mediated inflammatory signaling pathways.