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

Abstract

CONTEXT:

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.

OBJECTIVES:

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.

EXPERIMENTAL DESIGN:

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.

• Authors: Peng Hou, Ermal Bojdani, Mingzhao Xing
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 95 Issue 2 Pg. 820-8 (Feb 2010) ISSN: 1945-7197 [Electronic] United States
• PMID: 20008023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Hydroxamic Acids
• Intracellular Signaling Peptides and Proteins
• Iodine Radioisotopes
• Symporters
• Phosphorylcholine
• perifosine
• sodium-iodide symporter
• Vorinostat
• Thyrotropin
• MTOR protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Cell Line, Tumor
• Gene Expression Regulation
• Humans
• Hydroxamic Acids (pharmacology)
• Intracellular Signaling Peptides and Proteins (physiology)
• Iodine Radioisotopes (pharmacokinetics)
• MAP Kinase Signaling System
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Protein Serine-Threonine Kinases (physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Signal Transduction
• Symporters (analysis, genetics)
• TOR Serine-Threonine Kinases
• Thyroid Gland (metabolism)
• Thyroid Neoplasms (metabolism)
• Thyrotropin (pharmacology)
• Vorinostat