title: Troglitazone Stimulates Cancer Cell Uptake of 18F-FDG by Suppressing Mitochondrial Respiration and Augments Sensitivity to Glucose Restriction.
abstract: We evaluated how troglitazone influences cancer cell glucose metabolism and uptake of (18)F-FDG, and we investigated its molecular mechanism and relation to the drug's anticancer effect.
  
  
  METHODS
  Human T47D breast and HCT116 colon cancer cells that had been treated with troglitazone were measured for (18)F-FDG uptake, lactate release, oxygen consumption rate, mitochondrial membrane potential, and intracellular reactive oxygen species. Viable cell content was measured by sulforhodamine-B assays.
  
  
  RESULTS
  Treatment with 20 μM troglitazone for 1 h acutely increased (18)F-FDG uptake in multiple breast cancer cell lines, whereas HCT116 cells showed a delayed reaction. In T47D cells, the response occurred in a dose-dependent (threefold increase by 40 μΜ) manner independent of peroxisome proliferator-activated receptor-γ and was accompanied by a twofold increase of lactate production, consistent with enhanced glycolytic flux. Troglitazone-treated cells showed severe reductions of the oxygen consumption rate, indicating suppression of mitochondrial respiration, which was accompanied by significantly decreased mitochondrial membrane potential and increased concentration of reactive oxygen species. Troglitazone dose-dependently reduced T47D and HCT116 cell content, which was significantly potentiated by restriction of glucose availability. In T47D cells, cell reduction closely correlated with the magnitude of increase in relative (18)F-FDG uptake (r = 0.821, P = 0.001).
  
  
  CONCLUSIONS
  Troglitazone stimulates cancer cell uptake of (18)F-FDG through a shift of metabolism toward glycolytic flux, likely as an adaptive response to impaired mitochondrial oxidative respiration.
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Moon
authors.affiliation: Department of Nuclear Medicine, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and.
authors.forename: Kyung-Ho
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and.
authors.forename: Cung Hoa Thien
authors.initials: CH
authors.lastname: Quach
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and.
authors.forename: Jin-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and.
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and khnm.lee@samsung.com.
authors.forename: Kyung-Han
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D019788:Fluorodeoxyglucose F18; D020782:Matrix Metalloproteinases; D000077288:Troglitazone; D005947:Glucose; D010100:Oxygen
keywords: 18F-FDG; cancer; glycolysis; mitochondria; troglitazone