Abstract B23: Cysteine (C)-X-C receptor 4 induces oxidative stress through NADPH oxidase-2 in prostate cancer cells

Abstract

Abstract Reactive oxygen species (ROS), and the coupled oxidative stress, have long been implicated in the onset and progression of many cancers, including prostate cancer (PCa). One of the mechanisms by which ROS contributes to cancer is by acting as a second messenger, relaying signals from the cell surface to important signaling proteins, thereby regulating a variety of cellular processes. We have demonstrated that ROS increased the expression and activity of the chemokine (CXC) receptor, type 4 (CXCR4), which resulted in proliferation, invasion and trans-endothelial migration of PCa cells. Similarly, a study in human hepatoma cells revealed that CXCR4, and its ligand, stromal cell derived factor 1 alpha (SDF-1α), promoted ROS accumulation; however, the source (s) of ROS following growth factor stimulation have not been investigated. Identifying the sources of ROS that leads to oxidative stress in the tumor microenvironment remain areas of intense research. A recent study demonstrated that the increased ROS generation observed in PCa cell lines of varying aggressiveness was largely contributed by the NADPH oxidase family of enzymes. Herein, we observed that SDF-1α promoted ROS accumulation in C4-2 human PCa cells. We also established that NOX, an extramitochondrial ROS-generating system, was the primary source of ROS instead of the mitochondria. Moreover, expression of the isoform, NOX2, was preferentially regulated by CXCR4 at transcriptional and post-transcriptional levels. Finally, NOX2 expression correlated with PCa aggressiveness in microarray datasets. Therefore, we hypothesize that the SDF-1α /CXCR4 signaling axis mediates ROS production in PCa through NADPH-oxidases, resulting in oxidative stress that encourages tumor progression. Results generated from this study will further elucidate the mechanism (s) by which growth factor signaling promotes oxidative stress to enhance tumor development. Understanding the relationship between known cancer promoting elements, such as CXCR4, ROS and NOX, will facilitate the development of more comprehensive therapeutics to enhance current clinical strategies to combat cancer metastasis. Citation Format: Kia J. Jones, Mahandranauth A. Chetram, Danaya A. Bethea, Cimona V. Hinton. Cysteine (C)-X-C receptor 4 induces oxidative stress through NADPH oxidase-2 in prostate cancer cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B23.