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

Authors

  • Iman Osman MD,

    Corresponding author
    1. Department of Urology, New York University Cancer Institute, New York, New York
    2. Department of Medicine, New York University Cancer Institute, New York, New York
    • Department of Urology, New York University Cancer Institute, New York University Medical Center, 550 1st Avenue, H-100, New York, NY 10016
    Search for more papers by this author
    • Fax: (212) 951-3214.

  • Jie Dai PhD,

    1. Department of Urology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York
    Search for more papers by this author
  • Maryann Mikhail MD,

    1. Department of Urology, New York University Cancer Institute, New York, New York
    Search for more papers by this author
  • Daniel Navarro BS,

    1. Department of Urology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York
    Search for more papers by this author
  • Samir S. Taneja MD,

    1. Department of Urology, New York University Cancer Institute, New York, New York
    Search for more papers by this author
  • Peng Lee PhD,

    1. Department of Pathology, New York University Cancer Institute, New York, New York
    Search for more papers by this author
  • Paul Christos MPH, MS,

    1. Department of Biostatistics and Epidemiology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York
    Search for more papers by this author
  • Ruoqian Shen PhD,

    1. Department of Urology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York
    Search for more papers by this author
  • David M. Nanus MD

    1. Department of Urology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York
    2. Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York
    Search for more papers by this author

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.

Ancillary