Lentiviral Vector Neutral Endopeptidase Gene Transfer Suppresses Prostate Cancer Tumor Growth (Abstract)

Published in:
Cancer Gene Therapy.

Authors:
A. Horiguchi, R. Zheng, O. B. Goodman, Jr., R, Shen, H, Guan, L, B, Hersh, and D, M. Nanus

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/ g/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.

Correspondence:
Dr. D. M. Nanus, Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, 525 E, 68th Street, ST-359, New York, NY 10021, USA.
E-mail: dnanus@med.cornell.edu

(C) Cancer Gene Therapy.

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