Inverse Agonist of Estrogen-Related Receptor γ Enhances Sodium Iodide Symporter Function Through Mitogen-Activated Protein Kinase Signaling in Anaplastic Thyroid Cancer Cells
Anaplastic thyroid cancer (ATC), a rare thyroid cancer with poor prognosis, is associated with insufficient function of the sodium iodide symporter (NIS). Estrogen-related receptor γ (ERRγ) is a member of the orphan nuclear receptors with important functions in cell development and homeostasis. Howe...
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Veröffentlicht in: | Journal of Nuclear Medicine 2015-11, Vol.56 (11), p.1690-1696 |
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creator | Singh, Thoudam Debraj Jeong, Shin Young Lee, Sang-Woo Ha, Jeoung-Hee Lee, In-Kyu Kim, Seong Heon Kim, Jina Cho, Sung Jin Ahn, Byeong-Cheol Lee, Jaetae Jeon, Young Hyun |
description | Anaplastic thyroid cancer (ATC), a rare thyroid cancer with poor prognosis, is associated with insufficient function of the sodium iodide symporter (NIS). Estrogen-related receptor γ (ERRγ) is a member of the orphan nuclear receptors with important functions in cell development and homeostasis. However, there are no reports that demonstrate whether ERRγ is related to NIS function. Here, we evaluated the role of ERRγ in the regulation of NIS function in ATC cells using GSK5182, an inverse agonist of ERRγ.
Two ATC cell lines, BHT-101 and CAL62, were incubated with GSK5182 at various time points and doses. The NIS function in the ATC cells was serially assessed by their uptake of radioiodine. The effects of GSK5182 on ERRγ and the mitogen-activated protein (MAP) kinase pathway, as well as on NIS protein, were evaluated by immunoblot assay. To examine whether the GSK5182-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, the MAP kinase activity and levels of radioiodine uptake were determined after application of a mitogen-activated protein kinase kinase (MEK) inhibitor to GSK5182-treated cells. Finally, the cytotoxic effect of (131)I was determined by clonogenic assay.
Treatment with GSK5182 resulted in dose- and time-dependent increases in iodide uptake in ATC cells, which were accompanied by both the downregulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK) 1/2. Both the increased radioiodine uptake and ERK1/2 activation of ATC cells were completely inhibited by the specific MEK inhibitor. GSK5182 treatment enhanced the membrane localization of NIS in both ATC cell lines. Accordingly, preexposure to GSK5182 enhanced the cytotoxic effects of (131)I treatment in ATC cells.
These findings suggest that the inverse agonist of ERRγ enhances the responsiveness of radioiodine therapy by modulating NIS function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway. |
doi_str_mv | 10.2967/jnumed.115.160366 |
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Two ATC cell lines, BHT-101 and CAL62, were incubated with GSK5182 at various time points and doses. The NIS function in the ATC cells was serially assessed by their uptake of radioiodine. The effects of GSK5182 on ERRγ and the mitogen-activated protein (MAP) kinase pathway, as well as on NIS protein, were evaluated by immunoblot assay. To examine whether the GSK5182-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, the MAP kinase activity and levels of radioiodine uptake were determined after application of a mitogen-activated protein kinase kinase (MEK) inhibitor to GSK5182-treated cells. Finally, the cytotoxic effect of (131)I was determined by clonogenic assay.
Treatment with GSK5182 resulted in dose- and time-dependent increases in iodide uptake in ATC cells, which were accompanied by both the downregulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK) 1/2. Both the increased radioiodine uptake and ERK1/2 activation of ATC cells were completely inhibited by the specific MEK inhibitor. GSK5182 treatment enhanced the membrane localization of NIS in both ATC cell lines. Accordingly, preexposure to GSK5182 enhanced the cytotoxic effects of (131)I treatment in ATC cells.
These findings suggest that the inverse agonist of ERRγ enhances the responsiveness of radioiodine therapy by modulating NIS function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway.</description><identifier>ISSN: 0161-5505</identifier><identifier>EISSN: 1535-5667</identifier><identifier>EISSN: 2159-662X</identifier><identifier>DOI: 10.2967/jnumed.115.160366</identifier><identifier>PMID: 26338896</identifier><language>eng</language><publisher>United States</publisher><subject>Blotting, Western ; Cell Line, Tumor ; Estrogen Receptor Modulators - pharmacology ; Humans ; Iodine Radioisotopes - metabolism ; MAP Kinase Signaling System - drug effects ; Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Protein Kinase Inhibitors - pharmacology ; Receptors, Estrogen - drug effects ; Symporters - metabolism ; Tamoxifen - analogs & derivatives ; Tamoxifen - pharmacology ; Tamoxifen - therapeutic use ; Thyroid Carcinoma, Anaplastic - metabolism ; Thyroid Neoplasms - metabolism ; Tumor Stem Cell Assay</subject><ispartof>Journal of Nuclear Medicine, 2015-11, Vol.56 (11), p.1690-1696</ispartof><rights>2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1896-ec0e712e65bcf86f3ca27724e21ad04092477b06b1a0b2e83b7aed2f4aa843a03</citedby><cites>FETCH-LOGICAL-c1896-ec0e712e65bcf86f3ca27724e21ad04092477b06b1a0b2e83b7aed2f4aa843a03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26338896$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Singh, Thoudam Debraj</creatorcontrib><creatorcontrib>Jeong, Shin Young</creatorcontrib><creatorcontrib>Lee, Sang-Woo</creatorcontrib><creatorcontrib>Ha, Jeoung-Hee</creatorcontrib><creatorcontrib>Lee, In-Kyu</creatorcontrib><creatorcontrib>Kim, Seong Heon</creatorcontrib><creatorcontrib>Kim, Jina</creatorcontrib><creatorcontrib>Cho, Sung Jin</creatorcontrib><creatorcontrib>Ahn, Byeong-Cheol</creatorcontrib><creatorcontrib>Lee, Jaetae</creatorcontrib><creatorcontrib>Jeon, Young Hyun</creatorcontrib><title>Inverse Agonist of Estrogen-Related Receptor γ Enhances Sodium Iodide Symporter Function Through Mitogen-Activated Protein Kinase Signaling in Anaplastic Thyroid Cancer Cells</title><title>Journal of Nuclear Medicine</title><addtitle>J Nucl Med</addtitle><description>Anaplastic thyroid cancer (ATC), a rare thyroid cancer with poor prognosis, is associated with insufficient function of the sodium iodide symporter (NIS). Estrogen-related receptor γ (ERRγ) is a member of the orphan nuclear receptors with important functions in cell development and homeostasis. However, there are no reports that demonstrate whether ERRγ is related to NIS function. Here, we evaluated the role of ERRγ in the regulation of NIS function in ATC cells using GSK5182, an inverse agonist of ERRγ.
Two ATC cell lines, BHT-101 and CAL62, were incubated with GSK5182 at various time points and doses. The NIS function in the ATC cells was serially assessed by their uptake of radioiodine. The effects of GSK5182 on ERRγ and the mitogen-activated protein (MAP) kinase pathway, as well as on NIS protein, were evaluated by immunoblot assay. To examine whether the GSK5182-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, the MAP kinase activity and levels of radioiodine uptake were determined after application of a mitogen-activated protein kinase kinase (MEK) inhibitor to GSK5182-treated cells. Finally, the cytotoxic effect of (131)I was determined by clonogenic assay.
Treatment with GSK5182 resulted in dose- and time-dependent increases in iodide uptake in ATC cells, which were accompanied by both the downregulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK) 1/2. Both the increased radioiodine uptake and ERK1/2 activation of ATC cells were completely inhibited by the specific MEK inhibitor. GSK5182 treatment enhanced the membrane localization of NIS in both ATC cell lines. Accordingly, preexposure to GSK5182 enhanced the cytotoxic effects of (131)I treatment in ATC cells.
These findings suggest that the inverse agonist of ERRγ enhances the responsiveness of radioiodine therapy by modulating NIS function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway.</description><subject>Blotting, Western</subject><subject>Cell Line, Tumor</subject><subject>Estrogen Receptor Modulators - pharmacology</subject><subject>Humans</subject><subject>Iodine Radioisotopes - metabolism</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Receptors, Estrogen - drug effects</subject><subject>Symporters - metabolism</subject><subject>Tamoxifen - analogs & derivatives</subject><subject>Tamoxifen - pharmacology</subject><subject>Tamoxifen - therapeutic use</subject><subject>Thyroid Carcinoma, Anaplastic - metabolism</subject><subject>Thyroid Neoplasms - metabolism</subject><subject>Tumor Stem Cell Assay</subject><issn>0161-5505</issn><issn>1535-5667</issn><issn>2159-662X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kUtu2zAQQImiReOmPUA3BZfdyOVHJOWlYTiJ0RQt4nQtUNRIZiCRKkkF8Km66D1yptJxshpgPm9m8BD6TMmSraT69uDmEdolpWJJJeFSvkELKrgohJTqLVoQKmkhBBEX6EOMD4QQWVXVe3TBJOdVtZIL9HfnHiFEwOveOxsT9h3exhR8D664g0EnaPEdGJiSD_jpH966g3YGIt771s4j3uXQAt4fx8mHBAFfzc4k6x2-PwQ_9wf8w6Zn2jqnH595v4JPYB3-bp3Oq_e2d3qwrsc5t3Z6GnRM1mTAMXjb4s1pYcAbGIb4Eb3r9BDh00u8RL-vtvebm-L25_Vus74tDM1_FWAIKMpAisZ0ley40UwpVgKjuiUlWbFSqYbIhmrSMKh4ozS0rCu1rkquCb9EX8_cKfg_M8RUjzaafIF24OdYU8UJoRkpcis9t5rgYwzQ1VOwow7HmpL65Kk-e6qzp_rsKc98ecHPzan0OvEqhv8HH8CUEA</recordid><startdate>201511</startdate><enddate>201511</enddate><creator>Singh, Thoudam Debraj</creator><creator>Jeong, Shin Young</creator><creator>Lee, Sang-Woo</creator><creator>Ha, Jeoung-Hee</creator><creator>Lee, In-Kyu</creator><creator>Kim, Seong Heon</creator><creator>Kim, Jina</creator><creator>Cho, Sung Jin</creator><creator>Ahn, Byeong-Cheol</creator><creator>Lee, Jaetae</creator><creator>Jeon, Young Hyun</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201511</creationdate><title>Inverse Agonist of Estrogen-Related Receptor γ Enhances Sodium Iodide Symporter Function Through Mitogen-Activated Protein Kinase Signaling in Anaplastic Thyroid Cancer Cells</title><author>Singh, Thoudam Debraj ; Jeong, Shin Young ; Lee, Sang-Woo ; Ha, Jeoung-Hee ; Lee, In-Kyu ; Kim, Seong Heon ; Kim, Jina ; Cho, Sung Jin ; Ahn, Byeong-Cheol ; Lee, Jaetae ; Jeon, Young Hyun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1896-ec0e712e65bcf86f3ca27724e21ad04092477b06b1a0b2e83b7aed2f4aa843a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Blotting, Western</topic><topic>Cell Line, Tumor</topic><topic>Estrogen Receptor Modulators - pharmacology</topic><topic>Humans</topic><topic>Iodine Radioisotopes - metabolism</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Receptors, Estrogen - drug effects</topic><topic>Symporters - metabolism</topic><topic>Tamoxifen - analogs & derivatives</topic><topic>Tamoxifen - pharmacology</topic><topic>Tamoxifen - therapeutic use</topic><topic>Thyroid Carcinoma, Anaplastic - metabolism</topic><topic>Thyroid Neoplasms - metabolism</topic><topic>Tumor Stem Cell Assay</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Thoudam Debraj</creatorcontrib><creatorcontrib>Jeong, Shin Young</creatorcontrib><creatorcontrib>Lee, Sang-Woo</creatorcontrib><creatorcontrib>Ha, Jeoung-Hee</creatorcontrib><creatorcontrib>Lee, In-Kyu</creatorcontrib><creatorcontrib>Kim, Seong Heon</creatorcontrib><creatorcontrib>Kim, Jina</creatorcontrib><creatorcontrib>Cho, Sung Jin</creatorcontrib><creatorcontrib>Ahn, Byeong-Cheol</creatorcontrib><creatorcontrib>Lee, Jaetae</creatorcontrib><creatorcontrib>Jeon, Young Hyun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of Nuclear Medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singh, Thoudam Debraj</au><au>Jeong, Shin Young</au><au>Lee, Sang-Woo</au><au>Ha, Jeoung-Hee</au><au>Lee, In-Kyu</au><au>Kim, Seong Heon</au><au>Kim, Jina</au><au>Cho, Sung Jin</au><au>Ahn, Byeong-Cheol</au><au>Lee, Jaetae</au><au>Jeon, Young Hyun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inverse Agonist of Estrogen-Related Receptor γ Enhances Sodium Iodide Symporter Function Through Mitogen-Activated Protein Kinase Signaling in Anaplastic Thyroid Cancer Cells</atitle><jtitle>Journal of Nuclear Medicine</jtitle><addtitle>J Nucl Med</addtitle><date>2015-11</date><risdate>2015</risdate><volume>56</volume><issue>11</issue><spage>1690</spage><epage>1696</epage><pages>1690-1696</pages><issn>0161-5505</issn><eissn>1535-5667</eissn><eissn>2159-662X</eissn><abstract>Anaplastic thyroid cancer (ATC), a rare thyroid cancer with poor prognosis, is associated with insufficient function of the sodium iodide symporter (NIS). Estrogen-related receptor γ (ERRγ) is a member of the orphan nuclear receptors with important functions in cell development and homeostasis. However, there are no reports that demonstrate whether ERRγ is related to NIS function. Here, we evaluated the role of ERRγ in the regulation of NIS function in ATC cells using GSK5182, an inverse agonist of ERRγ.
Two ATC cell lines, BHT-101 and CAL62, were incubated with GSK5182 at various time points and doses. The NIS function in the ATC cells was serially assessed by their uptake of radioiodine. The effects of GSK5182 on ERRγ and the mitogen-activated protein (MAP) kinase pathway, as well as on NIS protein, were evaluated by immunoblot assay. To examine whether the GSK5182-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, the MAP kinase activity and levels of radioiodine uptake were determined after application of a mitogen-activated protein kinase kinase (MEK) inhibitor to GSK5182-treated cells. Finally, the cytotoxic effect of (131)I was determined by clonogenic assay.
Treatment with GSK5182 resulted in dose- and time-dependent increases in iodide uptake in ATC cells, which were accompanied by both the downregulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK) 1/2. Both the increased radioiodine uptake and ERK1/2 activation of ATC cells were completely inhibited by the specific MEK inhibitor. GSK5182 treatment enhanced the membrane localization of NIS in both ATC cell lines. Accordingly, preexposure to GSK5182 enhanced the cytotoxic effects of (131)I treatment in ATC cells.
These findings suggest that the inverse agonist of ERRγ enhances the responsiveness of radioiodine therapy by modulating NIS function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway.</abstract><cop>United States</cop><pmid>26338896</pmid><doi>10.2967/jnumed.115.160366</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Blotting, Western Cell Line, Tumor Estrogen Receptor Modulators - pharmacology Humans Iodine Radioisotopes - metabolism MAP Kinase Signaling System - drug effects Mitogen-Activated Protein Kinases - antagonists & inhibitors Protein Kinase Inhibitors - pharmacology Receptors, Estrogen - drug effects Symporters - metabolism Tamoxifen - analogs & derivatives Tamoxifen - pharmacology Tamoxifen - therapeutic use Thyroid Carcinoma, Anaplastic - metabolism Thyroid Neoplasms - metabolism Tumor Stem Cell Assay |
title | Inverse Agonist of Estrogen-Related Receptor γ Enhances Sodium Iodide Symporter Function Through Mitogen-Activated Protein Kinase Signaling in Anaplastic Thyroid Cancer Cells |
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