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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 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. Ets-1 was over-expressed using a stably-incorporated tetracycline-inducible expression vector in the ovarian cancer cell line 2008, which does not express detectable basal levels of Ets-1 protein. Microarray analysis of the effects of Ets-1 over-expression in these ovarian cancer cells shows that Ets-1 up-regulates key enzymes involved in glycolysis and associated feeder pathways, fatty acid metabolism, and antioxidant defense. In contrast, Ets-1 down-regulates genes involved in the citric acid cycle, electron transport chain, and mitochondrial proteins. At the functional level, 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 growth inhibition in a glucose-depleted culture environment. Collectively our findings demonstrate that Ets-1 is involved in the regulation of cellular metabolism and response to oxidative stress in ovarian cancer cells. [ABSTRACT FROM AUTHOR]

The mitochondria are unique cellular organelles that contain their own genome and, in conjunction with the nucleus, are able to transcribe and translate genes encoding components of the electron transport chain (ETC). To do so, the mitochondria must communicate with the nucleus via the production of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), which are produced as a byproduct of aerobic respiration within the mitochondria. Mitochondrial signaling is proposed to be altered in cancer cells, where the mitochondria are frequently found to harbor mutations within their genome and display altered functional characteristics leading to increased glycolysis. As signaling molecules, ROS oxidize and inhibit MAPK phosphatases resulting in enhanced proliferation and survival, an effect particularly advantageous to cancer cells. In terms of transcriptional regulation, ROS affect the phosphorylation, activation, oxidation, and DNA binding of transcription factors such as AP-1, NF-κB, p53, and HIF-1α, leading to changes in target gene expression. Increased ROS production by defective cancer cell mitochondria also results in the upregulation of the transcription factor Ets-1, a factor that has been increasingly associated with aggressive cancers. Les mitochondries sont des organites cellulaires uniques qui contiennent leur propre génome et, conjointement avec le noyau, sont capables de transcrire et de traduire les gènes codant pour les constituants de la chaîne de transport des électrons (CTÉ). Pour ce faire, les mitochondries doivent communiquer avec le noyau par la production d’espèces réactives de l’oxygène (ROS), comme le peroxyde d’hydrogène (H2O2), qui sont générées par un sous-produit de la respiration aérobie à l’intérieur des mitochondries. On postule que la signalisation mitochondriale est altérée dans les cellules cancéreuses, où l’on observe fréquemment des mutations dans le génome mitochondrial et des modifications dans les caractéristiques fonctionnelles des mitochondries causant une augmentation de la glycolyse. En tant que molécules de signalisation, les ROS oxydent et inhibent les MAPK phosphatases, ce qui provoque une augmentation de la prolifération et de la survie, un effet particulièrement avantageux pour les cellules cancéreuses. En matière de régulation transcriptionnelle, les ROS influent sur la phosphorylation, l’activation, l’oxydation, et la liaison de l’ADN de facteurs de transcription tels que AP-1, NF-κB, p53 et HIF-1α, entraînant des modifications dans l’expression de gènes cibles. L’augmentation de la production de ROS par les mitochondries défectueuses des cellules cancéreuses va aussi causer une activation du facteur de transcription Ets-1, un facteur de plus en plus associé aux cancers agressifs. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluated whether ets-1 is transcriptionally up-regulated by hydrogen peroxide in an ovarian carcinoma cell model and examined the element or elements within the ets-1 promoter involved in this response. Principal findings are given. Conclusions and significance of the study are discussed.