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Downregulation of phosphodiesterase 4B (PDE4B) activates protein kinase A and contributes to the progression of prostate cancer.

Abstract

BACKGROUND
Prostate cancer is the most commonly diagnosed non-cutaneous cancer in American men. Unfortunately, few successful therapies for castration-resistant prostate cancer (CRPC) exist. The protein kinase A (PKA) pathway is a critical mediator of cellular proliferation and differentiation in various normal and cancerous cells. However, the PKA activity and the mechanism of regulation in CRPC remain unclear. Then, in this study, we intended to reveal the PKA activity and the mechanism of regulation in CRPC.
METHODS
Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis, and cell proliferation assay were used to resolve the regulatory role of PKA in prostate cancer cell line, LNCaP and their derivatives.
RESULTS
cAMP-specific phosphodiesterase 4B (PDE4B) was downregulated and the PKA pathway was activated in castration-resistant LNCaP derivatives (CxR cells). Rolipram activated the PKA pathway via inhibition of PDE4B, resulting in AR transactivation while the PKA inhibitor, H89 reduced AR transactivation. In response to hydrogen peroxide and in hydrogen peroxide-resistant LNCaP derivatives (HPR50 cells) PDE4B was decreased and as a result PKA activity was increased. Moreover, PDE4B expression was reduced in advanced prostate cancer and PDE4B knockdown promoted castration-resistant growth of LNCaP cells.
CONCLUSIONS
Oxidative stress may suppress PDE4B expression and activate the PKA pathway. The PDE4B/PKA pathway contributed to progression of androgen-dependent prostate cancer to CRPC. This pathway may represent an attractive therapeutic molecular target.

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  • Publisher Full Text
  • Authors

    Kashiwagi E, Shiota M, Yokomizo A, Itsumi M, Inokuchi J, Uchiumi T, Naito S

    Institution

    Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

    Source

    The Prostate 72:7 2012 May 15 pg 741-51

    MeSH

    Cell Line, Tumor
    Cell Proliferation
    Cyclic AMP-Dependent Protein Kinases
    Cyclic Nucleotide Phosphodiesterases, Type 4
    Disease Progression
    Down-Regulation
    Humans
    Hydrogen Peroxide
    Isoquinolines
    Male
    Phosphodiesterase 4 Inhibitors
    Prostatic Neoplasms
    Protein Kinase Inhibitors
    Rolipram
    Sulfonamides

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22529021