Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hou
Peng
P
Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287, USA.
Bojdani
Ermal
E
Xing
Mingzhao
M
D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction; D027981:Symporters / Q000032:analysis / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D013961:Thyroid Gland / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology; D000077337:Vorinostat; D000099209:Sodium-Iodide Symporters
D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D019869:Phosphatidylinositol 3-Kinases; D010767:Phosphorylcholine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D027981:Symporters; D058570:TOR Serine-Threonine Kinases; D013972:Thyrotropin; D000077337:Vorinostat; D000099209:Sodium-Iodide Symporters; C105905:perifosine; C546842:MTOR protein, human