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

Abstract

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 p47production. 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-1A 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]

Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant hep G2 cells through a mitochondria-dependent oxidative stress mechanism

“…19,[21][22][23] The ROS generation was being heterogeneously distributed in various cellular compartments, but the highest amounts were concentrated in mitochondria. For this reason, sorafenib deserves to be referred to as a mitochondriatargeting drug.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Further, the pro-angiogenesis activity of tumor cells becomes crucial for their survival in a microenvironment progressively more hypoxic, for a continuous supply of nutrients and oxygen [116]. The hypoxic TME triggers, also through oxidative stress −as shown in ovarian and prostate cancers [117][118][119], the tumor production of angiogenetic factors such as vascular-endothelial-growth-factor (VEGF), by upregulating hypoxia-inducible factor-1α (HIF-1α) [120]. Interestingly, HIF-1α is able to limit ROS accumulation in tumor cells, thus promoting cancer progression at later stages, by limiting the production of acetyl-CoA (the key molecule entering the TCA cycle) from glycolysis [121] and fattyacid oxidation [122].…”

Free Radicals, Antioxidants and Disease

“…This has been shown in some type of cancers such as breast cancer [26]. Besides this oxidative stress may lead to activation of vascular endothelial growth factor and may induce angiogenesis which may further enhance malignancy [27][28][29].…”