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Extracellular Redox State Regulates Features Associated with Prostate Cancer Cell Invasion

¹ Pathology and Laboratory Medicine Service, William S. Middleton Memorial Veterans Hospital and Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; ² Department of Surgery, The University of Iowa and Veterans Affairs Medical Center; ³ Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa

Requests for reprints: Terry D. Oberley, William S. Middleton Memorial Veterans Hospital, Room A-35, 2500 Overlook Terrace, Madison, WI 53705. Phone: 608-256-1901, ext. 11722; Fax: 608-280-7087; E-mail: toberley{at}wisc.edu.

Key Words: Extracellular redox state • EC-SOD • cell invasion

We have examined the possible role of extracellular reduction-oxidation (redox) state in regulation of biological/biochemical features associated with prostate cancer cell invasion. DU145, PC-3, and RWPE1-derived human prostate cancer (WPE1-NB26) cell lines were used for the present in vitro analysis. Increasing levels of nitric oxide using S-nitroso-N-acetylpenicillamine resulted in a decrease in cell invasion ability, whereas increasing levels of extracellular superoxide radical (O₂^–) using xanthine/xanthine oxidase resulted in an increase in cell invasion ability in these three cell lines. WPE1-NB26 cells exhibited an increased glutathione/glutathione disulfide ratio in the medium in comparison with RWPE1 cells (immortalized but nonmalignant prostate epithelial cells), suggesting an alteration of extracellular redox state of WPE1-NB26 cells. We hypothesized that O₂^– production at or near the plasma membrane or in the adjacent extracellular matrix at least partially regulated prostate cancer cell invasion. Using adenovirus-mediated extracellular superoxide dismutase (EC-SOD) gene transduction to enzymatically decrease O₂^– levels, we showed that in the presence of heparin, adenovirus EC-SOD gene transduction resulted in an increase in the expression of EC-SOD outside the cells with resultant inhibition of cell invasion ability. This inhibition correlated with reduced metalloproteinase [matrix metalloproteinase (MMP) 2/membrane type 1-MMP] activities and increased levels of extracellular nitrite. Our results suggest a prominent role of extracellular redox status in regulation of cell invasion, which may provide opportunities for therapeutic interventions. [Cancer Res 2008;68(14):5820–6]

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