title: A novel radiotracer to image glycogen metabolism in tumors by positron emission tomography.
abstract: The high rate of glucose uptake to fuel the bioenergetic and anabolic demands of proliferating cancer cells is well recognized and is exploited with (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) to image tumors clinically. In contrast, enhanced glucose storage as glycogen (glycogenesis) in cancer is less well understood and the availability of a noninvasive method to image glycogen in vivo could provide important biologic insights. Here, we demonstrate that (18)F-N-(methyl-(2-fluoroethyl)-1H-[1,2,3]triazole-4-yl)glucosamine ((18)F-NFTG) annotates glycogenesis in cancer cells and tumors in vivo, measured by PET. Specificity of glycogen labeling was demonstrated by isolating (18)F-NFTG-associated glycogen and with stable knockdown of glycogen synthase 1, which inhibited (18)F-NFTG uptake, whereas oncogene (Rab25) activation-associated glycogen synthesis led to increased uptake. We further show that the rate of glycogenesis is cell-cycle regulated, enhanced during the nonproliferative state of cancer cells. We demonstrate that glycogen levels, (18)F-NFTG, but not (18)F-FDG uptake, increase proportionally with cell density and G1-G0 arrest, with potential application in the assessment of activation of oncogenic pathways related to glycogenesis and the detection of posttreatment tumor quiescence.
authors.affiliation: Authors' Affiliations: Comprehensive Cancer Imaging Centre; and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom; and Children's Medical Center Research Institute, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Witney
authors.forename: Laurence
authors.initials: L
authors.lastname: Carroll
authors.forename: Israt S
authors.initials: IS
authors.lastname: Alam
authors.forename: Anil
authors.initials: A
authors.lastname: Chandrashekran
authors.forename: Quang-Dé
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Roberta
authors.initials: R
authors.lastname: Sala
authors.forename: Robert
authors.initials: R
authors.lastname: Harris
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.forename: Roshan
authors.initials: R
authors.lastname: Agarwal
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D059447:Cell Cycle Checkpoints / Q000502:physiology; D045744:Cell Line, Tumor; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D020691:rab GTP-Binding Proteins / Q000235:genetics
chemical_list: C509763:Rab25 protein, human; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D006003:Glycogen; D020691:rab GTP-Binding Proteins