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Oxidative Stress Is Inherent in Prostate Cancer Cells and Is Required for Aggressive Phenotype

¹ Signal Transduction and Molecular Urology Laboratory-Program in Urosciences, Division of Urology, Department of Surgery, School of Medicine and ² University of Colorado Comprehensive Cancer Center, University of Colorado at Denver and Health Sciences Center, Denver, Colorado

Requests for reprints: Hari K. Koul, Division of Urology and Department of Surgery, University of Colorado at Denver and Health Sciences Center, School of Medicine, 4200 East Ninth Avenue, C-319, Denver, CO 80262. Phone: 303-315-2383; Fax: 303-315-1252; E-mail: hari.koul{at}uchsc.edu.

Key Words: oxidative stress • reactive oxygen species • prostate cancer • metastasis • mitogen-activated protein kinases

Reactive oxygen species (ROS) and the coupled oxidative stress have been associated with tumor formation. Several studies suggested that ROS can act as secondary messengers and control various signaling cascades. In the present studies, we characterized the oxidative stress status in three different prostate cancer cells (PC3, DU145, and LNCaP) exhibiting various degree of aggressiveness and normal prostate cells in culture (WPMY1, RWPE1, and primary cultures of normal epithelial cells). We observed increased ROS generation in cancer cells compared with normal cells, and that extramitochondrial source of ROS generator, NAD(P)H oxidase (Nox) systems, are associated with the ROS generation and are critical for the malignant phenotype of prostate cancer cells. Moreover, diphenyliodonium, a specific Nox inhibitor, blocked proliferation, modulated the activity of growth signaling cascades extracellular signal-regulated kinase (ERK)1/ERK2 and p38 mitogen-activated protein kinase as well as AKT protein kinaseB, and caused cyclin B–dependent G₂-M cell cycle arrest. We also observed higher degrees of ROS generation in the PC3 cells than DU145 and LNCaP, and that ROS generation is critical for migratory/invasiveness phenotypes. Furthermore, blocking of the ROS production rather than ROS neutralization resulted in decreased matrix metalloproteinase 9 activity as well as loss of mitochondrial potential, plausible reasons for decreased cell invasion and increased cell death. Taken together, these studies show, for the first time, the essential role of ROS production by extramitochondrial source in prostate cancer and suggest that therapies aimed at reducing ROS production might offer effective means of combating prostate cancer in particular, and perhaps other malignancies in general. [Cancer Res 2008;68(6):1777–85]

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