Abstract 986: Metabolic changes in ovarian cancer progression and mediation by sphingosine: The MOSE model
Authors: Angela S. Anderson, Matthew W. Hulver, Tim Brown, Madlyn I. Frisard, Paul C. Roberts, Eva M. Schmelz
Journal: Cancer Research (2011)

Abstract It is well established that tumor cells have an altered metabolic phenotype. Otto Warburg first demonstrated increased rates of glycolysis and decreased rates of oxidative phosphorylation in late-stage malignant cancer cells. It is however, unclear as to when, during the malignant progression of cancer cells, this switch takes place, what processes are involved, and the potential of these changes to serve as therapeutic targets for clinical intervention trials. Because of the late diagnosis that is associated with ovarian cancer, it is particularly imperative to identify when cellular changes are occurring to develop more efficacious detection and treatment strategies. We used our recently developed and characterized mouse ovarian surface epithelial (MOSE) cancer cells, spontaneously transformed in cell culture and progressed over time from a benign to a highly malignant phenotype both in vitro and in vivo, to study metabolic changes in the distinct disease stages. As ovarian cancer progresses from early to late stages, there were marked decreases in complete oxidation of both glucose and fatty acids. This was concurrent with increases in lactate excretion and 3H-deoxyglucose uptake by the late-stage cancer cells compared to the benign cells. Together, these metabolic changes shift the cells towards a more glycolytic phenotype. Additional studies revealed that these changes were accompanied by increases in pyruvate dehydrogenase activity and citrate synthase activity, indicating an increase in de novo fatty acid and cholesterol synthesis. Treatment of the MOSE cells with 1.5 μM sphingosine, a potent growth inhibitory and cytotoxic sphingolipid metabolite, partially reversed the glycolytic phenotype, decreasing citrate synthase activity and increasing citric acid cycle flux. The Seahorse Bioscience XF Analyzer was used to determine if the observed metabolic changes during MOSE progression are the result of mitochondrial function impairment. Both basal and uncoupled oxygen consumption rates (OCR) decreased as cancer progressed. OCR changes were partially restored after sphingosine treatment. The decreases in mitochondria OCR were supported by decreases in gene and protein expression of mitochondrial fusion and fission proteins as determined by real-time PCR and Western blotting. Taken together, our data confirm metabolic changes during progression and identify the stage specificity of these changes. These results validate the use of the MOSE cell model as an effective model for studying metabolic changes in cancer cell progression and the use of sphingosine as a chemotherapeutic agent to mediate these metabolic changes. Supported by NIH CA118846 to EMS and PCR. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 986. doi:10.1158/1538-7445.AM2011-986