18F-FDG与131I-碘化物甲状腺摄取信号转导的体外研究

In vitro studies on the signal transduction of thyroidal uptake of 18F-FDG and 131I-Iodide.

作者信息

Bläser Daniel, Maschauer Simone, Kuwert Torsten, Prante Olaf

机构信息

Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.

出版信息

J Nucl Med. 2006 Aug;47(8):1382-8.

PMID:16883020

Abstract

UNLABELLED

Glucose metabolism in radioiodine-negative metastases of differentiated thyroid carcinomas (DTC) may still be increased by thyroid-stimulating hormone (TSH) as demonstrated by PET with 18F-FDG. The mechanisms of signal transduction involved in that process are as yet not completely understood. Therefore, the aim of this study was to investigate the effects of TSH, of an analog of cyclic adenosine monophosphate (dibutyryl cyclic AMP (Bu)2cAMP), and of inhibitors of the phosphatidylinositol 3-kinase (PI3-kinase) and of the protein kinase A (PKA) on 18F-FDG and radioiodide uptake in the thyroid cell line FRTL-5.

METHODS

FRTL-5 cells were cultured in the presence of hormones with or without 1 mU/ mL TSH. Glucose carrier (GLUT-1) was determined by Western blot analysis. Cells were incubated with 0.5-1.0 MBq/mL 18F-FDG for 1 h or 18-37 kBq/mL 131I for 45 min, respectively, and tracer uptake was related to protein concentration. (Bu)2cAMP (1 mmol/L) was used as cAMP enhancer, H89 (0.25-25 micromol/L) as selective PKA inhibitor, and wortmannin (1 micromol/L) as inhibitor of PI3-kinase.

RESULTS

TSH induced a 2.6-fold +/- 0.5 increase of radioiodide uptake in FRTL-5 cells (P < 0.001, n = 8). The use of wortmannin inhibited TSH-induced uptake of 131I only moderately by 21.1% +/- 3.5% (P < 0.05, n = 8), whereas H89 markedly blocked the effect of TSH by 53.8% +/- 16.7% (P < 0.001, n = 8). TSH enhanced GLUT-1 concentration of FRTL-5 cell membrane preparations by a factor of 1.6 (n = 3). TSH-treated cells showed a 2.6-fold increased uptake of 18F-FDG (P < 0.001, n = 20). Stimulation by (Bu)2cAMP analogously increased 18F-FDG uptake (P < 0.001, n = 20). Wortmannin, but not H89, significantly inhibited TSH- and (Bu)2cAMP-stimulation of 18F-FDG uptake by 42% +/- 25% (P < 0.001, n = 20) and 42% +/- 31% (P < 0.001, n = 20), respectively.

CONCLUSION

The effect of TSH and cAMP on 18F-FDG uptake by FRTL-5 cells is mediated by PI3-kinase and not by PKA, thus differing from the mechanism of radioiodide accumulation of this cell line. This observation is one possible explanation for the persistence of TSH-dependent 18F-FDG uptake in radioiodine-negative metastases of DTC.

摘要

未标记

如用18F-FDG进行PET检查所示，分化型甲状腺癌（DTC）的放射性碘阴性转移灶中的葡萄糖代谢仍可能因促甲状腺激素（TSH）而增加。该过程中涉及的信号转导机制尚未完全明确。因此，本研究的目的是探讨TSH、环磷酸腺苷类似物（二丁酰环磷腺苷（Bu）2cAMP）、磷脂酰肌醇3激酶（PI3激酶）抑制剂和蛋白激酶A（PKA）对甲状腺细胞系FRTL-5摄取18F-FDG和放射性碘的影响。

方法

FRTL-5细胞在有或无1 mU/mL TSH的激素存在下培养。通过蛋白质印迹分析测定葡萄糖载体（GLUT-1）。细胞分别与0.5 - 1.0 MBq/mL 18F-FDG孵育1小时或与18 - 37 kBq/mL 131I孵育45分钟，示踪剂摄取量与蛋白质浓度相关。（Bu）2cAMP（1 mmol/L）用作cAMP增强剂，H89（0.25 - 25 μmol/L）用作选择性PKA抑制剂，渥曼青霉素（1 μmol/L）用作PI3激酶抑制剂。

结果

TSH使FRTL-5细胞中的放射性碘摄取增加2.6倍±0.5（P < 0.001，n = 8）。使用渥曼青霉素仅适度抑制TSH诱导的131I摄取，抑制率为21.1%±3.5%（P < 0.05，n = 8），而H89显著阻断TSH的作用，阻断率为53.8%±16.7%（P < 0.001，n = 8）。TSH使FRTL-5细胞膜制剂中的GLUT-1浓度提高1.6倍（n = 3）。经TSH处理的细胞显示18F-FDG摄取增加2.6倍（P < 0.001，n = 20）。（Bu）2cAMP刺激同样增加了18F-FDG摄取（P < 0.001，n = 20）。渥曼青霉素而非H89分别显著抑制TSH和（Bu）2cAMP刺激的18F-FDG摄取，抑制率分别为42%±25%（P < 0.001，n = 20）和42%±31%（P < 0.001，n = 20）。