Interferon-γ induces neuroendocrine differentiation of in vitro cultivated human prostate basal epithelial cells

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Prostatic neuroendocrine (NE) cells are intraglandular hybrid epithelial-neural-endocrine cells which express and secrete chromogranin, serotonin and numerous hormones and neuropeptides. Presumably NE cells regulate growth, differentiation and secretory activity of the prostatic epithelium through paracrine, endocrine and neurocrine mechanisms. They appear to differentiate from a common basal/precursor/stem cell which also gives rise to the secretory epithelium, but the responsible factors and mechanisms are still under investigation. The aim of this study was to evaluate the effects of type 1 (α, β) and type 2 (γ) interferons on human prostate basal cell (PrECs) proliferation and differentiation. Whereas α/β interferons increased the expression of the cell-cycle inhibitor p21CIP1 and inhibited DNA synthesis, IFN-γ led to increased apoptosis, cell-cycle inhibitor p27KIP1 expression and to differentiation of PrECs into NE-like cells. These morphological changes could neither be observed in stromal prostatic fibroblasts nor in prostate cancer cell lines LNCaP, PC-3 and BPH-1. 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. Moreover, they changed their cytokeratin expression pattern by upregulating low molecular weight cytokeratins (LMW-CK) 8 and 18 found predominantly in terminally differentiated secretory luminal/NE epithelial cells. Thus, IFN-γ produced locally in the aging prostate by basal cells and under proinflammatory conditions by infiltrating lymphocytes might influence NE cell differentiation and function and favour NE differentiation of tumor cells in hormone-refractory prostate cancer.