Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs

Abstract

Background: The MEK (mitogen-activated protein kinase)–inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS; SLC5A5) and associated miRNAs in thyroid cancer cells. Methods: Cytotoxicity was assessed by viability assay in TPC1, BCPAP, C643 and 8505C thyroid cancer cell lines. NIS, hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b-3p expression was determined by quantitative RT-PCR. NIS protein was detected by Western blot. Radioiodine uptake was performed with a Gamma counter. Results: Selumetinib caused a significant reduction of cell viability in all thyroid cancer cell lines. NIS transcript was restored by selumetinib in all cell lines. Its protein level was found up-regulated in TPC1 and BCPAP cells and down-regulated in C643 and 8505C cells after treatment with selumetinib. Treatment with selumetinib caused a down-regulation of hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p in TPC1 and BCPAP cells. In 8505C cells, a stable or down-regulated hsa-miR-146b-5p was detected after 1h and 48h of treatment. C643 cells showed stable or up-regulated hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p. Selumetinib treatment caused an increase of radioiodine uptake, which was significant in TPC1 cells. Conclusions: The study shows for the first time that selumetinib restores NIS by the inhibition of its related targeting miRNAs. Further studies are needed to clarify the exact mechanism activated by hsa-miR-146b-5p, hsa-miR-146b-3p and hsa-let7f-5p to stabilise NIS. Restoration of NIS could represent a milestone for the treatment of advanced RR-DTC.

Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment

“…Aberrant activation of intracellular signaling involving the MEK pathway contributes to thyroid tumorigenesis since MEK inhibition favors differentiation of radioiodine-refractory DTCs by restoring NIS expression [86,95,96]. Hence, a number of specific MEKi have been evaluated in preclinical and clinical studies including several samples/patients diagnosed with thyroid cancer [97,98,99].…”

New mechanisms of radioiodide uptake revealed via a novel high throughput drug screening approach in thyroid cancer

“…The regulation of NIS is principally accomplished via transcription factors, histone acetylation, post-translational modifications, hormonal signalling, and by iodide itself (4)(5)(6)(7)(8)(9)(10). These levels of control are generally disrupted in cancer by a plethora of mechanisms including altered histone acetylation and methylation of the NIS promoter (5,6), distorted miRNA expression (11)(12)(13), increased oxidative stress (14), and changed growth factor signalling (15,16), predominantly driven by the activation of oncogenes which directly stimulate the MAPK pathway. Thus in addressing repressed NIS function in thyroid cancer, this inherent multiplicity of regulation adds significantly to the complexity of potential therapeutic strategies.…”

Cell and Molecular Biology of Thyroid Disorders

“…This Special Issue covers combined in vitro and animal studies [26,27] and single in vitro studies [28,29,30,31] investigating mechanisms or drug-induced changes in different thyroid cancer types. Proteomics technology was used to detect differences between the hypothyroid and euthyroid state in human subjects [32].…”

“…A further in vitro study focused on the impact of the mitogen-activated protein kinase (MEK) inhibitor selumetinib in different thyroid carcinoma cell lines [30]. Selumetinib significantly reduced cell viability.…”

“…Future studies to clarify the mechanism activated by hsa-miR-146b-5p, hsa-miR-146b-3p, and hsa-let7f-5p to stabilize NIS should be performed. Restoration of the NIS might be a new option to treat advanced radioiodine refractory differentiated TC [30].…”