Loss of neutral endopeptidase and activation of protein kinase B (Akt) is associated with prostate cancer progression

Abstract

BACKGROUND. Neutral endopeptidase (NEP) is a cell‐surface peptidase that can regulate the activation of Akt kinase through catalytic‐dependent and independent mechanisms. NEP expression is absent in approximately 50% of prostate cancers. The authors investigated whether NEP loss in vivo would result in Akt phosphorylation and potentially contribute to prostate cancer progression by examining the interaction of NEP, Akt, and phosphatase and tensin homolog (PTEN) in a prostate xenograft model and in clinical specimens from patients with prostate cancer. METHODS. Using a tetracycline‐repressible expression system to express NEP in a tumor animal xenograft model, the effects of NEP were tested on tumor growth, Akt phosphorylation, and PTEN expression. The clinical relevance of NEP, phosphorylated Akt, and PTEN protein expression also was investigated in 204 patients who had undergone radical prostatectomy. RESULTS. The results indicated that the induction of NEP expression inhibited established xenograft tumor growth, diminished Akt phosphorylation, and increased PTEN protein levels. In humans, prostate cancers with complete loss of NEP expression were significantly more likely to express phosphorylated Akt (P = .02). Moreover, patients who had prostate cancers with concomitant loss of NEP and expression of phosphorylated Akt had an increased, independent risk of prostate‐specific antigen (PSA) recurrence (P = .03). In the study cohort, loss of PTEN protein expression did not correlated significantly with phosphorylated Akt or with patients' clinical outcome. CONCLUSIONS. The findings from this investigation demonstrated that NEP loss leads to Akt activation and contributes to the clinical progression of prostate cancer. Cancer 2006. © 2006 American Cancer Society.

Curcumin Inhibits the AKT/NF-κB Signaling via CpG Demethylation of the Promoter and Restoration of NEP in the N2a Cell Line

“…CUR-Induced NEP Upregulation Suppresses the AKT/NF-κB Pathway in N2a/APPswe Cells NEP has been demonstrated as an inhibitor of AKT (11). To determine whether upregulation of NEP induced by CUR mediates downregulation of activation of AKT and its downstream target NF-κB, the N2a/APPswe cells, engineered to over-produce Aβ (30), was used.…”

“…Subsequent studies have demonstrated that the pro-inflammatory factor NF-κB activated by several molecules including AKT is involved in the inflammation progress of AD (7,8). Besides the property of Aβ clearance in AD brains, NEP has also been reported to have negative regulatory effect on AKT signaling (11). In this study, we confirmed the ability of CUR treatment to inhibit AKT/NF-κB signaling by suppressing the activation of AKT and NF-κB in N2a/APPswe cells in NEP-dependent way.…”

“…Increasing evidence also indicates an important function of its inhibition in AKT activation (11,12). However, NEP, which alters with age, chronically decreases in AD brains (13).…”

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.…”

Helping the circulatory system heal itself: manipulating kinin signaling to promote neovascularization

“…Fewer studies have been performed to evaluate the benefit of inhibiting neutral endopeptidase, the major bradykinin-degrading enzyme in the heart [45,46]. A proangiogenic effect is indicated by studies reporting faster cancer progression to be associated with increased tumor vascularization under neutral endopeptidase inhibition [47,48]. Again, further studies in relevant models are necessary to understand the therapeutic potential for kininase blockers in vascularization of cardiovascular patients with and without diabetes.…”