Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells

TSH stimulation of sodium iodide symporter (NIS) expression in thyroid cancer promotes radioiodine uptake and is required to deliver an effective treatment dose. Activation of the insulin/phosphoinositide-3-kinase (PI3K) signaling pathway in TSH-stimulated thyroid cells reduces NIS expression at the transcriptional level. We, therefore, investigated the effects of PI3K pathway inhibition on iodide uptake and NIS expression in rat thyroid cell lines and human papillary thyroid cancer cells. A PI3K inhibitor, LY294002, significantly enhanced iodide uptake in two rat thyroid cell lines, FRTL-5 and PCCL3. The induction of Nis mRNA by LY294002 occurred 6 h after treatment, and was abolished by a translation inhibitor, cycloheximide. Expression of the transcription factor, Pax8, which stimulates NIS expression, was significantly increased in PCCL3 cells after LY294002 treatment. Removal of insulin abrogated the stimulatory effects of LY294002 on NIS mRNA and protein expression, but not on iodide uptake. These findings suggest that PI3K pathway inhibition results in post-translational stimulation of NIS. Inhibition of the PI3K pathway also significantly increased iodide uptake (∼3.5-fold) in BHP 2–7 papillary thyroid cancer cells (Ret/PTC1 positive), engineered to constitutively express NIS. Pharmacological inhibition of Akt, a factor stimulated by the PI3K pathway, increased exogenous NIS expression in BHP 2–7 as was seen with LY294002, but not increase the endogenous NIS expression in FRTL-5 cells. PI3K pathway inhibition increases functional NIS expression in rat thyroid cells and some papillary thyroid cancer cells by several mechanisms. PI3K inhibitors have the potential to increase radioiodide accumulation in some differentiated thyroid cancer.

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Induction of Thyroid Gene Expression and Radioiodine Uptake in Thyroid Cancer Cells by Targeting Major Signaling Pathways

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-1888 ◽

2010 ◽

Vol 95 (2) ◽

pp. 820-828 ◽

Cited By ~ 62

Author(s):

Peng Hou ◽

Ermal Bojdani ◽

Mingzhao Xing

Keyword(s):

Gene Expression ◽

Thyroid Cancer ◽

Cancer Cells ◽

Signaling Pathways ◽

Histone Deacetylase ◽

Sodium Iodide ◽

Therapeutic Potential ◽

Sodium Iodide Symporter ◽

Thyroid Cells ◽

Thyroid Cancer Cells

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.

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Retraction: Overexpression of PCDH8 inhibits proliferation and invasion, and induces apoptosis in papillary thyroid cancer cells

RSC Advances ◽

10.1039/d1ra90011k ◽

2021 ◽

Vol 11 (7) ◽

pp. 4163-4163

Author(s):

Laura Fisher

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Papillary Thyroid Cancer ◽

Papillary Thyroid ◽

Thyroid Cancer Cells ◽

Proliferation And Invasion

Retraction of ‘Overexpression of PCDH8 inhibits proliferation and invasion, and induces apoptosis in papillary thyroid cancer cells’ by Liang Chang et al., RSC Adv., 2018, 8, 18030–18037, DOI: 10.1039/C8RA02291G.

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