Abstract 43: Role of Ets-1 in the regulation of energy metabolism in cancer cells

Abstract Cancer cells predominantly utilize glycolysis for ATP production even in the presence of abundant oxygen, an environment that would normally result in energy production through oxidative phosphorylation. Although the molecular mechanism for this metabolic switch to aerobic glycolysis has not been fully elucidated, it is likely that mitochondrial damage to the electron transport chain and the resulting increased production of reactive oxygen species (ROS) are significant driving forces. In this study, we have investigated the role of the transcription factor Ets-1 in the regulation of mitochondrial function and metabolism. Microarray analysis of the effects of Ets-1 over-expression in 2008 ovarian cancer cells was conducted using the Affymetrix GeneChip® Human Gene 1.0ST Array. Our findings show that Ets-1 up-regulates key enzymes involved in glycolysis and associated feeder pathways, fatty acid metabolism, and antioxidant defense. Additionally, Ets-1 down-regulates genes involved in the citric acid cycle, electron transport chain, and mitochondrial proteins. These results were validated using real-time qRT-PCR. The mitochondrial activity of both ovarian cancer Ets-1 over-expressing and breast cancer Ets-1 down-regulating cells was evaluated by examining oxygen consumption using various electron transport chain inhibitors (Oxygraph 2k), growth in the absence of glucose, and sensitivity to the glycolytic inhibitor 2-DG. We have found that Ets-1 expression is directly correlated with cellular oxygen consumption whereby increased expression causes decreased oxygen consumption. Ets-1 over-expression also caused increased sensitivity to glycolytic inhibitors, as well as pronounced growth inhibition in a glucose-depleted culture environment. In the context of ROS production, Ets-1 up-regulation induces a significant reduction in H2O2 production, likely due to Ets-1-mediated up-regulation of antioxidants. Collectively, our findings show that Ets-1 is involved in the regulation of cellular metabolism and response to oxidative stress in cancer cells. (This work was supported by operating grants to GS provided by the Canadian Institutes of Health Research) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 43.