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Lentiviral vector neutral endopeptidase gene transfer suppresses prostate cancer tumor growth

Cancer Gene Therapy volume 14, pages 583–589 (2007)Cite this article

Abstract

Neprilysin (neutral endopeptidase, NEP) is a cell surface peptidase whose expression is lost in approximately 50% of prostate cancers (PC). NEP normally functions to inactivate peptides such as bombesin and endothelin-1, and potentiates the effects of the PTEN tumor suppressor via a direct protein–protein interaction. NEP loss contributes to PC progression. We investigated the therapeutic efficacy of using a lentiviral vector system to restore NEP expression in PC cells. Third-generation lentiviral vectors encoding wild-type NEP (L-NEP) or green fluorescent protein (L-GFP) were introduced into NEP-deficient 22RV1 PC cells. Cells infected with L-NEP or L-GFP at a multiplicity of infection of 10 demonstrated NEP enzyme activity of 1171.2±4.9 and 17.2±5.3 pmol/μg/min (P<0.0001), respectively. Cell viability, proliferation and invasion were each significantly inhibited in 22RV1 cells expressing NEP compared with control cells infected with L-GFP (P<0.01). Analysis of known downstream effects of NEP showed NEP-expressing cells exhibiting decreased Akt and focal adhesion kinase phosphorylation and increased PTEN protein expression. Finally, injection of L-NEP into established 22RV1 xenograft tumors significantly inhibited tumor growth (P<0.01). These experiments demonstrate that lentiviral NEP gene transfer is a novel targeted strategy for the treatment of NEP-deficient PC.

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Acknowledgements

This work was supported by NIH Grants CA80240(DMN), DA02243 (LBH), NCRR P20RR020171 (LBH) and DOD PC040758 (DMN), and the Robert H McCooey Memorial Cancer Research Fund (DMN).

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Authors and Affiliations

  1. Department of Urology, Urologic Oncology Research Laboratory, Weill Medical College of Cornell University, New York, NY, USA

    A Horiguchi, O B Goodman Jr, R Shen & D M Nanus

  2. Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA

    R Zheng, O B Goodman Jr & D M Nanus

  3. Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA

    H Guan & L B Hersh

Authors
  1. A Horiguchi
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  2. R Zheng
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  3. O B Goodman Jr
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  4. R Shen
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  6. L B Hersh
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  7. D M Nanus
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Correspondence to D M Nanus.

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Horiguchi, A., Zheng, R., Goodman, O. et al. Lentiviral vector neutral endopeptidase gene transfer suppresses prostate cancer tumor growth. Cancer Gene Ther 14, 583–589 (2007). https://doi.org/10.1038/sj.cgt.7701047

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