Extracellular Redox State Regulates Features Associated with Prostate Cancer Cell Invasion

Pathology and Laboratory Medicine Service, William S. Middleton Memorial Veterans Hospital, Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin 53705, USA.
Cancer Research (Impact Factor: 9.33). 07/2008; 68(14):5820-6. DOI: 10.1158/0008-5472.CAN-08-0162
Source: PubMed


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 (O(2)(*-)) 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 O(2)(*-) 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 O(2)(*-) 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.

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    • "The implications for ROS regulation are highly significant for cancer and other disease therapies because commonly used radio and chemotherapeutic drugs influence tumor outcome through ROS modulation. Some researchers are now using adenovirus containing SOD and CAT in the treatment of various cancers both in vitro and in vivo [106, 107]. Overexpression of MnSOD inhibits ras-induced transformation, modulated by intracellular ROS level [108]. "
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