Lentiviral Vector Neutral Endopeptidase Gene Transfer Suppresses Prostate Cancer Tumor Growth
Cancer Gene Therapy.
A. Horiguchi, R. Zheng, O. B. Goodman, Jr., R, Shen, H, Guan, L, B, Hersh, and D, M. Nanus
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.
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.
(C) Cancer Gene Therapy.
Posted by: Tressie Dalaya
Message posted by: Trevor M. D'Souza