Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287, USA.
J Clin Endocrinol Metab. 2010 Feb;95(2):820-8. doi: 10.1210/jc.2009-1888. Epub 2009 Dec 11.
Radioiodine ablation is commonly used to treat thyroid cancer, but a major challenge is often the loss of radioiodine avidity of the cancer caused by aberrant silencing of iodide-handling genes.
This study was conducted to test the therapeutic potential of targeting the aberrantly activated MAPK and PI3K/Akt/mTOR pathways and histone deacetylase to restore radioiodine avidity in thyroid cancer cells.
We tested the effects of specific inhibitors targeting these pathways/molecules that had established clinical applicability, including the MAPK kinase inhibitor RDEA119, mTOR inhibitor temsirolimus, Akt inhibitor perifosine, and histone deacetylase inhibitor SAHA, individually or in combinations, on the expression of iodide-handling genes and radioiodide uptake in a large panel of thyroid cancer cell lines.
The expression of a large number of iodide-handling genes could be restored, particularly the sodium/iodide symporter, TSH receptor, and thyroperoxidase, by treating cells with these inhibitors. The effect was particularly robust and synergistic when combinations of inhibitors containing SAHA were used. Robust expression of sodium/iodide symporter in the cell membrane, which plays the most important role in iodide uptake in thyroid cells, was confirmed by immunofluorescent microscopy. Radioiodide uptake by cells was correspondingly induced under these conditions. Thyroid gene expression and radioiodide uptake could both be further enhanced by TSH.
Targeting major signaling pathways could restore thyroid gene expression and radioiodide uptake in thyroid cancer cells. Further studies are warranted to test this therapeutic potential in restoring radioiodine avidity of thyroid cancer cells for effective ablation treatment.
放射性碘消融术常用于治疗甲状腺癌，但一个主要的挑战是，由于碘处理基因的异常沉默，癌症通常会失去对放射性碘的摄取能力。
本研究旨在测试针对异常激活的 MAPK 和 PI3K/Akt/mTOR 通路以及组蛋白去乙酰化酶以恢复甲状腺癌细胞对放射性碘摄取能力的治疗潜力。
我们测试了针对这些通路/分子的特异性抑制剂的效果，这些抑制剂具有既定的临床适用性，包括 MAPK 激酶抑制剂 RDEA119、mTOR 抑制剂替西罗莫司、Akt 抑制剂 perifosine 和组蛋白去乙酰化酶抑制剂 SAHA，单独或联合使用，对大量甲状腺癌细胞系中碘处理基因的表达和放射性碘摄取的影响。
通过用这些抑制剂处理细胞，可以恢复大量碘处理基因的表达，特别是钠/碘转运体、TSH 受体和甲状腺过氧化物酶。当使用包含 SAHA 的抑制剂组合时，效果尤其显著和协同。通过免疫荧光显微镜证实了细胞膜中钠/碘转运体的强烈表达，钠/碘转运体在甲状腺细胞摄取碘中起着最重要的作用。在这些条件下，细胞的放射性碘摄取相应地被诱导。在 TSH 存在的情况下，甲状腺基因的表达和放射性碘的摄取都可以进一步增强。
靶向主要信号通路可以恢复甲状腺癌细胞中的甲状腺基因表达和放射性碘摄取。需要进一步研究来测试这种治疗潜力，以恢复甲状腺癌细胞对放射性碘的摄取能力，从而实现有效的消融治疗。
