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GROWTH, DIFFERENTIATION, AND APOPTOSIS
Departments of 1Internal Medicine, 2General Surgery, and 3Emergency Medicine and the Cannon Research Center, Carolinas Medical Center, Charlotte, North Carolina 28232; 4Department of Pathology Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322; 6Division of Respiratory, Critical Care, and Occupational (Pulmonary) Medicine, University of Utah, Salt Lake City, Utah 84132; 7Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717; 8Genomics Collaborative, Incorporated, Blue Bell, Pennsylvania 19422; and 5Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710
Submitted 13 November 2002 ; accepted in final form 1 April 2003
Reactive oxygen species (ROS) appear to play an important role in regulating growth and survival of prostate cancer. However, the sources for ROS production in prostate cancer cells have not been determined. We report that ROS are generated by intact American Type Culture Collection DU 145 cells and by their membranes through a mechanism blocked by NAD(P)H oxidase inhibitors. ROS are critical for growth in these cells, because NAD(P)H oxidase inhibitors and antioxidants blocked proliferation. Components of the human phagocyte NAD(P)H oxidase, p22phox and gp91phox, as well as the Ca2+ concentration-responsive gp91phox homolog NOX5 were demonstrated in DU 145 cells by RT-PCR and sequencing. Although the protein product for p22phox was not detectable, both gp91phox and NOX5 were identified throughout the cell by immunostaining and confocal microscopy and NOX5 immunostaining was enhanced in a perinuclear location, corresponding to enhanced ROS production adjacent to the nuclear membrane imaged by 2',7'-dichlorofluorescin diacetate oxidation. The calcium ionophore ionomycin dramatically stimulated ferricytochrome c reduction in cell media, further supporting the importance of NOX5 for ROS production. Antisense oligonucleotides for NOX5 inhibited ROS production and cell proliferation in DU 145 cells. In contrast, antisense oligonucleotides to p22phox or gp91phox did not impair cell growth. Inhibition of ROS generation with antioxidants or NAD(P)H oxidase inhibitors increased apoptosis in cells. These results indicate that ROS generated by the newly described NOX5 oxidase are essential for prostate cancer growth, possibly by providing trophic intracellular oxidant tone that retards programmed cell death.
superoxide anion; diphenylene iodonium; p22phox; gp91phox; adenosine 3',5'-cyclic monophosphate response element; caspases
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