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Reactive Oxygen Species Regulate Angiogenesis and Tumor Growth through Vascular Endothelial Growth Factor

¹ Mary Babb Randolph Cancer Center, and Departments of Microbiology, Immunology and Cell Biology and ² Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia; and ³ Lab of Reproductive Medicine, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China

Requests for reprints: Bing-Hua Jiang, Mary Babb Randolph Cancer Center, and Department of Microbiology, Immunology and Cell Biology, West Virginia University, 1801 Health Sciences South, Morgantown, WV 26506. Phone: 304-293-5949; Fax: 304-293-4667; E-mail: bhjiang{at}hsc.wvu.edu.

Reactive oxygen species (ROS) are associated with multiple cellular functions such as cell proliferation, differentiation, and apoptosis. However, the direct roles of endogenous ROS production still remain to be elucidated. In this study, we found that high levels of ROS were spontaneously produced by ovarian and prostate cancer cells. This elevated ROS production was inhibited by NADPH oxidase inhibitor diphenylene iodonium (DPI) and mitochondria electron chain inhibitor rotenone in the cells. To further analyze the source of ROS production, we found that ovarian cancer cells have much higher expression of NOX4 NADPH oxidase, and that specific inhibition of NADPH oxidase subunit p47^phox diminished ROS production. To analyze the functional relevance of ROS production, we showed that ROS regulated hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) expression in ovarian cancer cells. Elevated levels of endogenous ROS were required for inducing angiogenesis and tumor growth. NOX4 knockdown in ovarian cancer cells decreased the levels of VEGF and HIF-1 and tumor angiogenesis. This study suggests a new mechanism of higher ROS production in ovarian cancer cells and provides strong evidence that endogenous ROS play an important role for cancer cells to induce angiogenesis and tumor growth. This information may be useful to understand the new mechanism of cancer cells in inducing tumorigenesis and to develop new therapeutic strategy by targeting ROS signaling in human cancer in the future. [Cancer Res 2007;67(22):10823–30]