NEUTRAL ENDOPEPTIDASE-24.11 LOSS IN METASTATIC HUMAN PROSTATE-CANCER CONTRIBUTES TO ANDROGEN-INDEPENDENT PROGRESSION

Neutral endopeptidase 24.11 (NEP) is a cell-surface enzyme expressed b y prostatic epithelial cells that cleaves and inactivates neuropeptide s implicated in the growth of androgen-independent prostate cancer (PC ). We report that NEP expression and catalytic activity are lost in vi tro in androgen-independent but not androgen-dependent PC cell lines. In vivo, NEP protein expression is commonly decreased in cancer cells of metastatic PC specimens from patients with androgen-independent but not androgen-dependent PC. Overexpression of NEP in androgen-independ ent PC cells or incubation with recombinant NEP inhibits PC cell growt h. Furthermore, in androgen-dependent PC cells, expression of NEP is t ranscriptionally regulated by androgen and decreases with androgen wit hdrawal. These data suggest that decreased NEP expression, common in a ndrogen-independent PCs, is facilitated by the elimination of androgen s, and that NEP loss plays an important role in the development of and rogen-independent PC by allowing Pt cells to use mitogenic neuropeptid es as an alternate source to androgen in order to stimulate cell proli feration.