Interferon-γ induces neuroendocrine-like differentiation of human prostate basal-epithelial cells

BACKGROUND Prostatic neuroendocrine (NE) cells are intraglandular hybrid epithelial‐neural‐endocrine cells that express and secrete numerous hormones and neuropeptides, which presumably regulate growth, differentiation, and secretory activity of the prostatic epithelium. This specialized cell type appears to differentiate from a common basal/precursor/stem cell that also gives rise to the secretory epithelium. In order to elucidate mechanisms of NE‐differentiation the effects of type 1 (α, β) and type 2 (γ) interferons (IFNs) on human prostate basal cells (PrECs) were evaluated. METHODS AND RESULTS Application of α/β IFN increased the expression of the cell‐cycle inhibitor p21CIP1 and inhibited DNA synthesis, while only IFN‐γ led to increased apoptosis, cell‐cycle inhibitor p27KIP1 upregulation, and differentiation of PrECs into NE‐like cells. In vitro differentiated NE‐like cells expressed the glycolytic enzyme neuron‐specific enolase (NSE) and chromogranin A (CgA), known markers of NE‐cells in vivo in the prostate. These NE‐like cells also changed cytokeratin (CK) expression patterns by upregulating CK 8/18, predominantly found in terminally‐differentiated secretory luminal/NE epithelial cells. CONCLUSIONS IFN‐γ produced locally in the prostate by basal cells and, under proinflammatory conditions, by infiltrating lymphocytes could support NE cell differentiation and play a role in NE differentiation processes of tumor cells in hormone‐refractory prostate cancer. © 2005 Wiley‐Liss, Inc.