Regulation of keratinocyte growth factor receptor and androgen receptor inepithelial cells of the human prostate

Purpose: Stromal-epithelial interactions of growth factors and the androgen receptor may have implications for the pathophysiology of benign and neopl astic transformation of the human adult prostate. We investigated a possibl e interaction of keratinocyte growth factor with its receptor as well as wi th the androgen receptor signaling pathway in human prostatic epithelial ce lls. Materials and Methods: Human prostatic epithelial cells were obtained from explant primary culture, established in DU145 cell conditioned medium and m aintained in keratinocyte serum-free medium with supplements. Epithelial ce lls were characterized by light and electron microscopy, and immunocytochem ical study using epithelial and mesenchymal markers. Androgen receptor, ker atinocyte growth factor receptor and keratinocyte growth factor messenger R NA expression was measured by polymerase chain reaction (PCR). The response to 0.01 to 10 nM. dihydrotestosterone, 10 muM. flutamide and 1 to 1,000 ng ./ml. keratinocyte growth factor was tested by [H-3] thymidine assay. The d ifference in keratinocyte growth factor receptor and androgen receptor gene expression after treatment with and without keratinocyte growth factor and flutamide were determined by quantitative multiplex PCR and quantitated us ing densitometry analysis. Results: Immunocytochemical and electron microscopy characterization reveal ed typical epithelial differentiation. PCR showed keratinocyte growth facto r receptor and androgen receptor expression in epithelial cultured cells bu t no keratinocyte growth factor expression. Epithelial cells showed a signi ficant time and dose dependent stimulation of cell proliferation with kerat inocyte growth factor and dihydrotestosterone (p <0.05). When combined with the antiandrogen flutamide the effect of 100 ng./ml. keratinocyte growth f actor was significantly decreased (p <0.05). At 100 ng./ml. keratinocyte gr owth factor quantitative multiplex PCR revealed stimulated keratinocyte gro wth factor receptor and androgen receptor messenger RNA expression. Conclusions: These results show that keratinocyte growth factor up-regulate s the keratinocyte growth factor and androgen receptors in the absence of a ndrogen. Thus, the androgen signaling pathway may be activated by growth fa ctors such as keratinocyte growth factor in an androgen deficient environme nt.