title: Bioenergetic properties of human sarcoma cells help define sensitivity to metabolic inhibitors.
abstract: Sarcomas represent a diverse group of malignancies with distinct molecular and pathological features. A better understanding of the alterations associated with specific sarcoma subtypes is critically important to improve sarcoma treatment. Renewed interest in the metabolic properties of cancer cells has led to an exploration of targeting metabolic dependencies as a therapeutic strategy. In this study, we have characterized key bioenergetic properties of human sarcoma cells in order to identify metabolic vulnerabilities between sarcoma subtypes. We have also investigated the effects of compounds that inhibit glycolysis or mitochondrial respiration, either alone or in combination, and examined relationships between bioenergetic parameters and sensitivity to metabolic inhibitors. Using 2-deoxy-D-glucose (2-DG), a competitive inhibitor of glycolysis, oligomycin, an inhibitor of mitochondrial ATP synthase, and metformin, a widely used anti-diabetes drug and inhibitor of complex I of the mitochondrial respiratory chain, we evaluated the effects of metabolic inhibition on sarcoma cell growth and bioenergetic function. Inhibition of glycolysis by 2-DG effectively reduced the viability of alveolar rhabdomyosarcoma cells vs. embryonal rhabdomyosarcoma, osteosarcoma, and normal cells. Interestingly, inhibitors of mitochondrial respiration did not significantly affect viability, but were able to increase sensitivity of sarcomas to inhibition of glycolysis. Additionally, inhibition of glycolysis significantly reduced intracellular ATP levels, and sensitivity to 2-DG-induced growth inhibition was related to respiratory rates and glycolytic dependency. Our findings demonstrate novel relationships between sarcoma bioenergetics and sensitivity to metabolic inhibitors, and suggest that inhibition of metabolic pathways in sarcomas should be further investigated as a potential therapeutic strategy.
authors.affiliation: Molecular Pharmacology Branch; Leidos Biomedical Research, Inc.; Frederick National Laboratory for Cancer Research; Frederick, MD USA.
authors.forename: Sameer H
authors.initials: SH
authors.lastname: Issaq
authors.affiliation: Division of Cancer Treatment and Diagnosis; National Cancer Institute; Rockville, MD USA.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
authors.affiliation: Molecular Pharmacology Branch; Leidos Biomedical Research, Inc.; Frederick National Laboratory for Cancer Research; Frederick, MD USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Monks
mesh_terms: D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D009840:Oligomycins / Q000494:pharmacology; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology
chemical_list: D007004:Hypoglycemic Agents; D009840:Oligomycins; D008687:Metformin; D003847:Deoxyglucose; D025261:Mitochondrial Proton-Translocating ATPases; D042967:Electron Transport Complex I
keywords: 2-DG; bioenergetics; metformin; osteosarcoma; rhabdomyosarcoma; sarcoma