Regulation of uptake of 18F-FDG by a follicular human thyroid cancer cell line with mutation-activated K-ras

J Nucl Med. 2009 Aug;50(8):1364-70. doi: 10.2967/jnumed.109.062331.


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.

Conclusion: (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.

MeSH terms

  • Adenoma / diagnostic imaging
  • Adenoma / genetics
  • Adenoma / metabolism*
  • Cell Line, Tumor
  • Enzyme Activation
  • Fluorodeoxyglucose F18 / pharmacokinetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mutation / genetics
  • Radionuclide Imaging
  • Radiopharmaceuticals / pharmacokinetics
  • Thyroid Neoplasms / diagnostic imaging*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Radiopharmaceuticals
  • Fluorodeoxyglucose F18
  • ras Proteins