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

Iman Osman, Jie Dai, Maryann Mikhail, Daniel Navarro, Samir S. Taneja, Peng Lee, Paul Christos, Ruoqian Shen, David M. Nanus

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Pages (from-to)2628-2636
    Number of pages9
    JournalCancer
    Volume107
    Issue number11
    DOIs
    StatePublished - Dec 1 2006

    Keywords

    • Akt
    • Neutral endopeptidase
    • Phosphatase and tensin homolog
    • Prostate cancer
    • Tumor suppressor protein

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Osman, I., Dai, J., Mikhail, M., Navarro, D., Taneja, S. S., Lee, P., Christos, P., Shen, R., & Nanus, D. M. (2006). Loss of neutral endopeptidase and activation of protein kinase B (Akt) is associated with prostate cancer progression. Cancer, 107(11), 2628-2636. https://doi.org/10.1002/cncr.22312