title: Metabolic vulnerabilities in endometrial cancer.
abstract: Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumors themselves has been largely understudied. Comparing human endometrial tumors and cells with their nonmalignant counterparts, we found that upregulation of the glucose transporter GLUT6 was more closely associated with the cancer phenotype than other hallmark cancer genes, including hexokinase 2 and pyruvate kinase M2. Importantly, suppression of GLUT6 expression inhibited glycolysis and survival of endometrial cancer cells. Glycolysis and lipogenesis were also highly coupled with the cancer phenotype in patient samples and cells. To test whether targeting endometrial cancer metabolism could be exploited as a therapeutic strategy, we screened a panel of compounds known to target diverse metabolic pathways in endometrial cells. We identified that the glycolytic inhibitor, 3-bromopyruvate, is a powerful antagonist of lipogenesis through pyruvylation of CoA. We also provide evidence that 3-bromopyruvate promotes cell death via a necrotic mechanism that does not involve reactive oxygen species and that 3-bromopyruvate impaired the growth of endometrial cancer xenografts.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Frances L
authors.initials: FL
authors.lastname: Byrne
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Victoria, Australia.
authors.forename: Ivan K H
authors.initials: IK
authors.lastname: Poon
authors.affiliation: Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Modesitt
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Tomsig
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
authors.forename: Jenny D Y
authors.initials: JD
authors.lastname: Chow
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
authors.forename: Marin E
authors.initials: ME
authors.lastname: Healy
authors.affiliation: Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia.
authors.forename: William D
authors.initials: WD
authors.lastname: Baker
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, Virginia.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Atkins
authors.affiliation: Departments of Women's Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Johnathan M
authors.initials: JM
authors.lastname: Lancaster
authors.affiliation: Departments of Women's Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Marchion
authors.affiliation: Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Kelle H
authors.initials: KH
authors.lastname: Moley
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. Center for Cell Clearance, University of Virginia, Charlottesville, Virginia.
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. Cancer Center, University of Virginia, Charlottesville, Virginia.
authors.forename: Jill K
authors.initials: JK
authors.lastname: Slack-Davis
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia. Cancer Center, University of Virginia, Charlottesville, Virginia. Department of Medicine, University of Virginia, Charlottesville, Virginia. klh8st@virginia.edu.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Hoehn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002470:Cell Survival; D003065:Coenzyme A / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism; D005260:Female; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009336:Necrosis / Q000139:chemically induced; D011770:Pyruvate Kinase / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051246:Glucose Transport Proteins, Facilitative; D011773:Pyruvates; D017382:Reactive Oxygen Species; C411811:SLC2A9 protein, human; C017092:bromopyruvate; D006593:Hexokinase; D011770:Pyruvate Kinase; D003065:Coenzyme A