Nerve growth factor induces the re-expression of functional androgen receptors and p75(NGFR) in the androgen-insensitive prostate cancer cell line DU145

Section of Pharmacology, Department of Biomedical Sciences and Biotechnologies, Brescia University Medical School, Via Valsabbina 19, 25123 Brescia, Italy. sigala@med.unibs.it

BACKGROUND: One of the paracrine/autocrine factors regulating prostate growth and differentiation is nerve growth factor (NGF). The role of NGF and its receptors in the prostate, however, remains controversial. We have shown that NGF treatment of human prostate cancer cell lines reduced their tumorigenicity, both in vitro and in vivo. OBJECTIVE: To investigate the involvement of NGF as a differentiation factor in prostate cancer cells. DESIGN: We exposed the androgen-independent/androgen receptor (AR)-negative prostate cancer cell line DU145 to NGF to study whether this neurotrophin could revert DU145 cells to a less malignant phenotype. METHODS: DU145 cells were treated with NGF, then ARs and NGF receptor p75(NGFR) expression and telomerase activity were studied. Finally, we investigated whether re-expression of ARs could restore the androgen sensitivity in this cell line. RESULTS AND CONCLUSIONS: NGF treatment induced a reversion of DU145 cells to a less malignant phenotype, characterized by the re-expression of ARs and p75(NGFR) NGF receptors. Re-expression of ARs restored the androgen sensitivity, as suggested by the fact that exposure to dihydrotestosterone stimulated the growth of NGF-treated DU145 cells. This effect was blocked by androgen antagonist drugs, such as hydroxyflutamide and cyproterone acetate, which also induced apoptotic death of NGF-treated cells. The hypothesis that a differentiation pathway is activated by exogenous NGF in DU145 cells is also supported by findings indicating that NGF-treated DU145 cells expressed a low telomerase activity, as a result of a decrease in human telomerase reverse transcriptase transcription.