Targeting Androgen Receptor to Suppress Macrophage-induced EMT and Benign Prostatic Hyperplasia (BPH) Development

Abstract

Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain 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 prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-β2, were increased, and administration of anti-TGF-β2 neutralizing antibody during co-culture suppressed 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 that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk 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.

Development of animal models underlining mechanistic connections between prostate inflammation and cancer

“…The sustained activation of AR expressed by epithelial and adjacent stromal fibromuscular cells in the prostate gland, which plays critical functions in the modulation of stromal-epithelial interactions for the maintaining of normal prostate homeostasis, also can promote the development of prostatic inflammatory lesions, including inflammation-associated BPH and PCs [80][81][82][83][84] . For instance, it has been observed using an in vitro cell co-culture system that immortalized and non-tumorigenic BPH-1 human prostate epithelial cells significantly increased the migration of THP-1 macrophages which, in turn, induced the EMT marker expression, such as N-cadherin, snail and TGF-β2, in BPH-1 cells as well as their sphere-forming ability [80] .…”

“…For instance, it has been observed using an in vitro cell co-culture system that immortalized and non-tumorigenic BPH-1 human prostate epithelial cells significantly increased the migration of THP-1 macrophages which, in turn, induced the EMT marker expression, such as N-cadherin, snail and TGF-β2, in BPH-1 cells as well as their sphere-forming ability [80] . Moreover, the exogenous expression of AR in BPH-1-AR also promoted the THP-1 cell migration and enhanced EMT marker expression and sphere-forming capacity of BPH-1-AR cells relative to BPH-1-vector cells used as control [80] .…”

Development of a Novel Method to Detect Prostate Cancer Circulating Tumor Cells (CTCs) Based on Epithelial-Mesenchymal Transition Biology

“…AR also upregulates NKX3-1, which represses TWIST1 via binding to the TWIST1 promoter [66]. Contrary to the above findings, which suggest that AR inhibits EMT, ectopic expression of AR in BPH-1 cells induces EMT, whereas knockdown of AR downregulates EMT markers [67], suggesting that AR may play a different role in culture conditions than within the tumor microenvironment. The connections between AR signaling and EP are likely complex and context dependent, and many signaling pathways including β-catenin, Src kinase, …”

Resveratrol suppresses the epithelial-to-mesenchymal transition in PC-3 cells by down-regulating the PI3K/AKT signaling pathway

“…The transcription factors that regulate the EMT are expressed in numerous malignant cancers. Increasing evidence and research suggests that the EMT has important functions in the malignant transformation of prostate cancer, and it also induces cancer cells to invade and migrate (Hance et al 2012;Lu et al 2012). Therefore, the EMT may be a potential therapeutic target, and inhibition of the EMT may be a promising method to treat cancer.…”