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Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs
Sabine Wächter1, Annette Wunderlich2, Brandon H Greene3
1Department of Visceral Thoracic and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043 Marburg, Germany. seckhard@med.uni-marburg.de.
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.
Insights
The MEK inhibitor selumetinib restored sodium iodide symporter (NIS) expression in thyroid cancer cells by down-regulating specific microRNAs. This finding offers a potential new avenue for treating advanced radioiodine-refractory differentiated thyroid cancer (RR-DTC).
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Radioiodine-refractory differentiated thyroid cancer (RR-DTC) poses treatment challenges.
- MEK inhibitor selumetinib has shown promise in increasing radioiodine uptake in a subset of RR-DTC patients.
- The precise molecular mechanisms underlying selumetinib's effect on radioiodine uptake require further elucidation.
Purpose of the Study:
- To investigate the impact of selumetinib on sodium iodide symporter (NIS) expression in thyroid cancer cells.
- To analyze the role of specific microRNAs (miRNAs) in mediating selumetinib's effects on NIS expression.
- To explore the potential of selumetinib as a therapeutic agent for RR-DTC by assessing its effects on NIS and radioiodine uptake.
Main Methods:
- Utilized four distinct thyroid cancer cell lines (TPC1, BCPAP, C643, 8505C) for in vitro studies.
- Assessed cell viability using standard cytotoxicity assays.
- Quantified expression levels of NIS, hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b-3p via quantitative RT-PCR.
- Determined NIS protein levels using Western blot analysis and measured radioiodine uptake with a Gamma counter.
Main Results:
- Selumetinib significantly reduced cell viability across all tested thyroid cancer cell lines.
- NIS transcript levels were restored by selumetinib treatment in all cell lines.
- NIS protein expression showed differential regulation: up-regulated in TPC1 and BCPAP, down-regulated in C643 and 8505C cells.
- Selumetinib induced down-regulation of hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b-3p in TPC1 and BCPAP cells.
- Radioiodine uptake increased following selumetinib treatment, with a significant effect observed in TPC1 cells.
Conclusions:
- Selumetinib demonstrates the ability to restore NIS expression, potentially through the inhibition of specific targeting miRNAs.
- The study highlights the intricate relationship between selumetinib, miRNAs (hsa-miR-146b-5p, hsa-miR-146b-3p, hsa-let7f-5p), and NIS stabilization.
- Further research is warranted to fully elucidate the mechanisms by which these miRNAs influence NIS expression.
- Restoration of NIS presents a promising therapeutic strategy for patients with advanced RR-DTC.
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