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

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 so...

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Autores principales: Wächter, Sabine, Wunderlich, Annette, Greene, Brandon H., Roth, Silvia, Elxnat, Moritz, Fellinger, Sebastian A., Verburg, Frederik A., Luster, Markus, Bartsch, Detlef K., Di Fazio, Pietro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073679/
https://www.ncbi.nlm.nih.gov/pubmed/30018229
http://dx.doi.org/10.3390/ijms19072077
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author Wächter, Sabine
Wunderlich, Annette
Greene, Brandon H.
Roth, Silvia
Elxnat, Moritz
Fellinger, Sebastian A.
Verburg, Frederik A.
Luster, Markus
Bartsch, Detlef K.
Di Fazio, Pietro
author_facet Wächter, Sabine
Wunderlich, Annette
Greene, Brandon H.
Roth, Silvia
Elxnat, Moritz
Fellinger, Sebastian A.
Verburg, Frederik A.
Luster, Markus
Bartsch, Detlef K.
Di Fazio, Pietro
author_sort Wächter, Sabine
collection PubMed
description 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.
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spelling pubmed-60736792018-08-13 Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs Wächter, Sabine Wunderlich, Annette Greene, Brandon H. Roth, Silvia Elxnat, Moritz Fellinger, Sebastian A. Verburg, Frederik A. Luster, Markus Bartsch, Detlef K. Di Fazio, Pietro Int J Mol Sci Article 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. MDPI 2018-07-17 /pmc/articles/PMC6073679/ /pubmed/30018229 http://dx.doi.org/10.3390/ijms19072077 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wächter, Sabine
Wunderlich, Annette
Greene, Brandon H.
Roth, Silvia
Elxnat, Moritz
Fellinger, Sebastian A.
Verburg, Frederik A.
Luster, Markus
Bartsch, Detlef K.
Di Fazio, Pietro
Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs
title Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs
title_full Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs
title_fullStr Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs
title_full_unstemmed Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs
title_short Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs
title_sort selumetinib activity in thyroid cancer cells: modulation of sodium iodide symporter and associated mirnas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073679/
https://www.ncbi.nlm.nih.gov/pubmed/30018229
http://dx.doi.org/10.3390/ijms19072077
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