title: Regulation of uptake of 18F-FDG by a follicular human thyroid cancer cell line with mutation-activated K-ras.
abstract: Dedifferentiation of thyroid carcinoma is accompanied by increased accumulation of the PET tracer (18)F-FDG. The molecular mechanisms responsible for this phenomenon are poorly understood. Therefore, we studied the regulation of (18)F-FDG uptake by the human follicular thyroid carcinoma cell line ML-1 and the as-yet-unknown oncogene expression of that cell line. The data obtained in ML-1 were compared with those of a well-differentiated thyroid cell line of rat origin (FRTL-5).
  
  
  METHODS
  The expression of the thyroid-stimulating hormone (TSH) receptor was investigated by immunocytochemistry, and the expression of the glucose transporters (GLUTs) was determined by Western blotting. Mutation analysis of ML-1 was performed for K-ras codons 12 and 13. The effect of TSH on intracellular cAMP levels was determined by a competitive enzyme immunoassay. Cells were incubated with (18)F-FDG (0.5-1.0 MBq/mL) for 1 h, and tracer uptake was related to protein concentration. The effects of bovine TSH, the cAMP analog (Bu)(2)cAMP, and the phosphatidylinositol-3-kinase (PI3-kinase) inhibitor LY294002 on (18)F-FDG uptake were investigated.
  
  
  RESULTS
  The TSH receptor was present in both cell lines. FRTL-5 clearly expressed GLUT-1 and also GLUT-4. In ML-1 only, the expression of GLUT-3 was detected. TSH and (Bu)(2)cAMP had a significant effect on (18)F-FDG uptake or GLUT-1 expression in FRTL-5, but not in ML-1 cells. PI3-kinase inhibition by LY294002 downregulated (18)F-FDG uptake in FRTL-5 by 58% +/- 9% (n = 6) and in ML-1 by 26% +/- 5% (n = 42, both P < 0.05). Mutation analysis of ML-1 cells revealed a Gly12Ser point mutation at codon 12 of the K-ras gene.
  
  
  CONCLUSIONS
  (18)F-FDG uptake in the thyroid carcinoma cell line ML-1 is no longer regulated by TSH or cAMP or mediated by GLUT-1. However, in this cell line, this variable is still governed to some extent by PI3-kinase located downstream to the constitutively active K-ras in the Ras-PI3-kinase-Akt pathway. These data suggest that increases in (18)F-FDG uptake in thyroid carcinomas observed in vivo by PET may reflect activation of intracellular signal transduction cascades by oncogenes.
authors: Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Friedrich-Alexander University, Erlangen, Germany.
authors: Olaf
authors: O
authors: Prante
authors: Simone
authors: S
authors: Maschauer
authors: Valerie
authors: V
authors: Fremont
authors: Julia
authors: J
authors: Reinfelder
authors: Robert
authors: R
authors: Stoehr
authors: Mariusz
authors: M
authors: Szkudlinski
authors: Bruce
authors: B
authors: Weintraub
authors: Arndt
authors: A
authors: Hartmann
authors: Torsten
authors: T
authors: Kuwert
mesh_terms: D000236:Adenoma / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation / Q000235:genetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D018631:ras Proteins