Neutral Endopeptidase Protein Expression and Prognosis in Localized Prostate Cancer

Abstract

Purpose: Neutral endopeptidase (NEP) is a cell-surface peptidase that inactivates neuropeptide growth factors implicated in prostate cancer progression. The clinical significance of decreased NEP expression observed in prostate cancer is unclear. We investigated whether decreased NEP expression in localized prostate cancers is associated with prostate-specific antigen (PSA) relapse after radical prostatectomy.Experimental Design: NEP expression patterns were examined by immunohistochemistry in 223 men, who underwent radical prostatectomy between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) with available representative tissues and adequate follow up. We also examined whether hypermethylation of the NEP promoter contributes to down-regulation of NEP protein expression in a subset of patients that showed decreased NEP expression (n ‫؍‬ 22).Results: Three patterns of NEP expression were observed: (a) membranous expression similar to benign prostate epithelium (n ‫؍‬ 82; 37%); (b) complete loss of NEP expression in prostate cancer compared with adjacent benign prostate glands (n ‫؍‬ 105; 47%); and (c) heterogeneous NEP expression (n ‫؍‬ 36; 16%). In a multivariate analysis, complete loss of NEP expression was associated with PSA relapse after controlling for grade, stage, pretreatment PSA, and race simultaneously (hazard ratio, 1.99; 95% confidence interval, 1.13-3.52; two-sided 2 P ‫؍‬ 0.017). In addition, DNA hypermethylation of the NEP promoter was frequently (73%) identified in a subset of 22 of cases that showed decreased NEP expression.Conclusion: Our data suggest that decreased NEP expression might contribute to progression of localized prostate cancer after surgery. Data also suggest that methylation is an important mechanism of NEP protein silencing. Larger prospective studies are required for confirmation.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Possible NEP implication in cancer mechanism has been postulated on the basis of the NEP identity with the common acute lymphoblastic leukemia antigen CD10, a leukemia associated antigen expressed in lymphoid precursors and germinal B cells, and of an alteration of its expression and activity in a variety of malignancies (Carrel et al, 1983;Tran-Paterson et al, 1989). In particular, NEP plays a pivotal role in the development and progression of androgen-independent-prostate cancer (PC) (Osman et al, 2004;Papandreou et al, 1998;Usmani et al, 2000), since its substrates, such as bombesin and endothelin-1, are implicated at various stages of PC (Albrecht et al, 2004;Freedland et al, 2003). In recent years, NEP has also emerged as an important tumor suppressor gene product and its biological role has been not only related to its enzymatic function, but also to a direct protein-protein interaction (Sumitomo et al, 2005).…”

Neutral endopeptidase inhibits prostate cancer tumorigenesis by reducing FGF-2-mediated angiogenesis

“…4,7,8 Loss of NEP in vivo in primary prostate cancers correlates with increased Akt phosphorylation, and predicts biochemical relapse in patients who have undergone radical prostatectomy. 6,9 Together, these studies suggest that NEP loss contributes to prostate cancer progression.…”

“…Expression of NEP is frequently decreased or lost in prostate cancers via hypermethylation of the NEP promoter or following androgen withdrawal. [4][5][6] Loss of NEP in prostate cancer cell lines results in increased peptide-mediated cell growth, cell migration and invasion, and ligandindependent activation of the insulin-like growth factor-1 receptor leading to Akt phosphorylation. 4,7,8 Loss of NEP in vivo in primary prostate cancers correlates with increased Akt phosphorylation, and predicts biochemical relapse in patients who have undergone radical prostatectomy.…”

Lentiviral vector neutral endopeptidase gene transfer suppresses prostate cancer tumor growth

“…[2][3][4] NEP is a 90-110-kDa cell surface peptidase normally expressed on prostatic epithelial cells. NEP functions to catalytically inactivate a variety of peptides that contribute to PC progression, including endothelin-1, bombesin and basic fibroblast growth factor (FGF-2).…”