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Regulation of Uptake of ¹⁸F-FDG by a Follicular Human Thyroid Cancer Cell Line with Mutation-Activated K-Ras

¹ Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Friedrich-Alexander University, Erlangen, Germany; ² Trophogen Inc., Rockville, Maryland; and ³ Institute of Pathology, Friedrich-Alexander University, Erlangen, Germany

Correspondence: For correspondence or reprints contact: Torsten Kuwert, Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany.E-mail: torsten.kuwert{at}uk-erlangen.de

Dedifferentiation of thyroid carcinoma is accompanied by increased accumulation of the PET tracer ¹⁸F-FDG. The molecular mechanisms responsible for this phenomenon are poorly understood. Therefore, we studied the regulation of ¹⁸F-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 ¹⁸F-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)₂cAMP, and the phosphatidylinositol-3-kinase (PI3-kinase) inhibitor LY294002 on ¹⁸F-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)₂cAMP had a significant effect on ¹⁸F-FDG uptake or GLUT-1 expression in FRTL-5, but not in ML-1 cells. PI3-kinase inhibition by LY294002 downregulated ¹⁸F-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: ¹⁸F-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 ¹⁸F-FDG uptake in thyroid carcinomas observed in vivo by PET may reflect activation of intracellular signal transduction cascades by oncogenes.

Key Words: thyroid carcinoma • ¹⁸F-FDG • PET • oncogene • K-ras

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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