title: Metabolic changes during ovarian cancer progression as targets for sphingosine treatment.
abstract: Tumor cells often exhibit an altered metabolic phenotype. However, it is unclear as to when this switch takes place in ovarian cancer, and the potential for these changes to serve as therapeutic targets in clinical prevention and intervention trials. We used our recently developed and characterized mouse ovarian surface epithelial (MOSE) cancer progression model to study metabolic changes in distinct disease stages. As ovarian cancer progresses, complete oxidation of glucose and fatty acids were significantly decreased, concurrent with increases in lactate excretion and (3)H-deoxyglucose uptake by the late-stage cancer cells, shifting the cells towards a more glycolytic phenotype. These changes were accompanied by decreases in TCA flux but an increase in citrate synthase activity, providing substrates for de novo fatty acid and cholesterol synthesis. Also, uncoupled maximal respiration rates in mitochondria decreased as cancer progressed. Treatment of the MOSE cells with 1.5 μM sphingosine, a bioactive sphingolipid metabolite, decreased citrate synthase activity, increased TCA flux, decreased cholesterol synthesis and glycolysis. Together, our data confirm metabolic changes during ovarian cancer progression, indicate a stage specificity of these changes, and suggest that multiple events in cellular metabolism are targeted by exogenous sphingosine which may be critical for future prevention trials.
authors.affiliation: Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, VA 24060, United States.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Anderson
authors.forename: Paul C
authors.initials: PC
authors.lastname: Roberts
authors.forename: Madlyn I
authors.initials: MI
authors.lastname: Frisard
authors.forename: Ryan P
authors.initials: RP
authors.lastname: McMillan
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Brown
authors.forename: Michael H
authors.initials: MH
authors.lastname: Lawless
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Hulver
authors.forename: Eva M
authors.initials: EM
authors.lastname: Schmelz
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D019069:Cell Respiration; D002784:Cholesterol / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects; D016895:Culture Media, Serum-Free; D018450:Disease Progression; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D013110:Sphingosine / Q000494:pharmacology*
chemical_list: D016895:Culture Media, Serum-Free; D005227:Fatty Acids; D019344:Lactic Acid; D002784:Cholesterol; D002950:Citrate (si)-Synthase; D005947:Glucose; D013110:Sphingosine; D010100:Oxygen