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Enzymatically active prostate-specific antigen promotes growth of human prostate cancers

Authors

  • Simon A. Williams,

    Corresponding author
    1. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    • The Brady Urological Research Institute, Park 202C, 600 North Wolfe Street, Baltimore 21287, MD.
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  • Christine A. Jelinek,

    1. Department of Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Ivan Litvinov,

    1. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Robert J. Cotter,

    1. Department of Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • John T. Isaacs,

    1. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Samuel R. Denmeade

    1. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Conflict of interest: The authors declare no conflict of interest.

Abstract

BACKGROUND

Prostate specific antigen (PSA) is the best-known member of the kallikrein-related peptidase family, with an established role as a prostatic disease biomarker. Although it is produced at high levels by all stages of prostate cancer, it is uncertain if PSA plays a role in prostate cancer initiation and progression. We decided to investigate the impact of PSA and its enzymatic activity on tumor cell growth rates.

METHODS

A gene-specific shRNA lentiviral construct reduced endogenous PSA expression in the LNCaP human prostate cancer cell line. Resulting changes in growth rates in vitro and in vivo were determined. Using a mass spectroscopy-based approach, alterations to the LNCaP proteome due to reduced PSA were measured. Finally, to evaluate the importance of PSA's proteolytic activity, the PSA-null Du145 human prostate cancer cell line was engineered to express either enzymatically inactive pro-PSA (WT) or a furin-activated variant (FR) with high enzymatic activity. The resulting clones were evaluated for PSA-induced changes in growth rates in vivo and in vitro.

RESULTS

Lowered PSA levels dramatically reduced LNCaP growth rates. Expressing active PSA (FR), but not the inactive WT variant, conferred a growth advantage on Du145 cells. Proteomics analysis revealed global changes to the LNCaP proteome as a result of reduced PSA expression.

CONCLUSIONS

These studies demonstrate the importance of PSA to prostate cancer cell growth. We also show that the enzymatic activity of PSA confers an enhanced growth rate to human prostate cancer cells, suggesting a causal role in prostate cancer progression. Prostate 71:1595–1607, 2011. © 2011 Wiley-Liss, Inc.

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