title: 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.
authors.affiliation: Department of Urology, New York University Cancer Institute, New York, New York, USA. iman.osman@med.nyu.edu
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.forename: Jie
authors.initials: J
authors.lastname: Dai
authors.forename: Maryann
authors.initials: M
authors.lastname: Mikhail
authors.forename: Daniel
authors.initials: D
authors.lastname: Navarro
authors.forename: Samir S
authors.initials: SS
authors.lastname: Taneja
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
authors.forename: Paul
authors.initials: P
authors.lastname: Christos
authors.forename: Ruoqian
authors.initials: R
authors.lastname: Shen
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
mesh_terms: D000818:Animals; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000473:pathology; D009368:Neoplasm Transplantation; D015260:Neprilysin / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011446:Prospective Studies; D017430:Prostate-Specific Antigen; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen; D015260:Neprilysin