Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1783344242629804032 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6073679 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT wachtersabine selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas AT wunderlichannette selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas AT greenebrandonh selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas AT rothsilvia selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas AT elxnatmoritz selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas AT fellingersebastiana selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas AT verburgfrederika selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas AT lustermarkus selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas AT bartschdetlefk selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas AT difaziopietro selumetinibactivityinthyroidcancercellsmodulationofsodiumiodidesymporterandassociatedmirnas |