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 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.
Highlights
Over 50 years ago, Otto Warburg first proposed that mitochondrial injury that leads to depressed electron transport chain function and respiratory defects is an important step in the development and progression of carcinogenesis [1,2]
Four to five percent of the O2 consumed by oxidative phosphorylation in the mitochondria is normally converted to reactive oxygen species; defects to the electron transport chain system in cancer cells would result in excessive reactive oxygen species formation [8,9,10]
Using high throughput genomic analysis, we have found that Ets-1 regulates, either directly or indirectly, several important genes involved in mitochondrial metabolic and antioxidant defense pathways in our Ets-1 over-expression ovarian cancer cell model
Summary
Over 50 years ago, Otto Warburg first proposed that mitochondrial injury that leads to depressed electron transport chain function and respiratory defects is an important step in the development and progression of carcinogenesis [1,2]. Known as the Warburg effect, 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 [2,6]. The increased production of reactive oxygen species, H2O2, by cancer cells is likely the result of mitochondrial dysfunction, as mitochondria are considered to be the predominant cellular source of reactive oxygen species [8]. Four to five percent of the O2 consumed by oxidative phosphorylation in the mitochondria is normally converted to reactive oxygen species; defects to the electron transport chain system in cancer cells would result in excessive reactive oxygen species formation [8,9,10]. Produced, H2O2 can act as a signaling molecule by oxidizing cysteine molecules on proteins, activating several signaling pathways including MAPK, as well as several transcription factors including AP-1, p53, NF-kB, and Ets-1 [11,12,13,14,15]
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