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1 Department of Internal Medicine, Carolinas Medical Center, Charlotte, NC, USA
2 Department of General Surgery, Carolinas Medical Center, Charlotte, NC, USA
3 Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC, USA
4 Department of Pathology Laboratory Medicine, Emory University, Atlanta, GA, USA
5 Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
6 Department of Medicine, University of Utah, Salt Lake City, UT, USA
7 Department of Veterinary Molecular Biology, Montana State University, Bozeman, MT, USA
8 Genomics Collaborative, Inc., Blue Bell, PA, USA
9 Department of Pathology Laboratory Medicine, Emory University, Atlanta, GA, USA; Department of Pathology Laboratory Medicine, Emory University, Atlanta, GA, USA
* To whom correspondence should be addressed. E-mail: tkennedy{at}carolinas.org.
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 Ameriacan Type Culture Collection DU145 cells and by their membranes through a mechanism blocked by NAD(P)H oxidase inhibitors. ROS are critical for growth in these cells, since 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+]-responsive gp91phox homologue NOX5 were demonstrated in DU145 cells by RT-PCR and sequencing. While 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 peri-nuclear location, corresponding to enhanced ROS production adjacent to the nuclear membrane imaged by 2',7'-dichlorofluorescin diacetate (DCFH-DA) 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 DU145 cells. In contrast, antisense oligonucleotides to p22phox or gp91phox did not impair cell growth. Inhibition of ROS generation using 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.
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