Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs

Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs

Bibliographic Details
Main Author: Lakshmanan, Aparna
Language:English
Published: The Ohio State University / OhioLINK 2015
Subjects:
Biomedical Research
Molecular Biology
Oncology
Thyroid cancer
Sodium Iodide Symporter
Radioactive iodide uptake
Akt
Akti1-2
Apigenin
p38MAPK
PKC-delta
PI3K
GDC-0941
Iodide efflux rate
MEK
Hsp90
BRAF
RET-PTC
TGF-beta
miR-339-5p
miR-195
Rottlerin
OSU-15
SREBP
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1429407914
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Biomedical Research
Molecular Biology
Oncology
Thyroid cancer
Sodium Iodide Symporter
Radioactive iodide uptake
Akt
Akti1-2
Apigenin
p38MAPK
PKC-delta
PI3K
GDC-0941
Iodide efflux rate
MEK
Hsp90
BRAF
RET-PTC
TGF-beta
miR-339-5p
miR-195
Rottlerin
OSU-15
SREBP
spellingShingle Biomedical Research
Molecular Biology
Oncology
Thyroid cancer
Sodium Iodide Symporter
Radioactive iodide uptake
Akt
Akti1-2
Apigenin
p38MAPK
PKC-delta
PI3K
GDC-0941
Iodide efflux rate
MEK
Hsp90
BRAF
RET-PTC
TGF-beta
miR-339-5p
miR-195
Rottlerin
OSU-15
SREBP
Lakshmanan, Aparna
Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs
author Lakshmanan, Aparna
author_facet Lakshmanan, Aparna
author_sort Lakshmanan, Aparna
title Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs
title_short Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs
title_full Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs
title_fullStr Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs
title_full_unstemmed Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs
title_sort modulation of sodium iodide symporter-mediated thyroidal radioiodide uptake by small molecule inhibitors, natural plant-based products and micrornas
publisher The Ohio State University / OhioLINK
publishDate 2015
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914
work_keys_str_mv AT lakshmananaparna modulationofsodiumiodidesymportermediatedthyroidalradioiodideuptakebysmallmoleculeinhibitorsnaturalplantbasedproductsandmicrornas
_version_ 1719438095075508224
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu14294079142021-08-03T06:30:17Z Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs Lakshmanan, Aparna Biomedical Research Molecular Biology Oncology Thyroid cancer Sodium Iodide Symporter Radioactive iodide uptake Akt Akti1-2 Apigenin p38MAPK PKC-delta PI3K GDC-0941 Iodide efflux rate MEK Hsp90 BRAF RET-PTC TGF-beta miR-339-5p miR-195 Rottlerin OSU-15 SREBP Thyroid cancer is the most common endocrine cancer and its incidence rates continue to rise. Papillary thyroid cancer (PTC) is the most common type and it is generally treatable with surgery followed by radioactive iodine (RAI) therapy. Thyrotropin (TSH)-stimulated, Sodium/Iodide Symporter (NIS)-mediated RAI uptake (RAIU) is the basis for RAI therapy. While most patients show good prognosis, a subset of patients with advanced thyroid cancer do not benefit from RAI therapy due to reduced NIS expression/function. The objective of this study was to investigate the molecular mechanisms of NIS modulation and to identify novel reagents that selectively increase RAIU in thyroid cells, such that the subset of patients could benefit from RAI therapy. Most common genetic alterations in PTCs are the BRAF(V600E) mutation that activates MEK/ERK signaling and RET/PTC rearrangement that activates both PI3K/Akt/mTOR and Ras/BRAF/MEK/ERK pathways. Hsp90 is a chaperone to many of these oncoproteins. TGF-beta is a cytokine in invasive fronts of thyroid tumors, which also activates MEK/ERK. These signaling nodes not only contribute to tumor progression but also result in reduced NIS expression/function. Here we report that among cell culture-grade small molecule inhibitors tested, Akt inhibitor (Akti1/2) increased TSH-stimulated RAIU to the greatest extent in PCCl3 rat thyroid cells, when compared to inhibitors of MEK, PI3K or Hsp90. We identified Apigenin, a plant-derived flavonoid that further increased RAIU by increasing iodide influx rate in combination with Akti1/2 and this required p38 MAPK activity, but not PKC-delta. The effect was confirmed in BRAF(V600E) or RET/PTC1-expressing PCCl3 cells, and in primary thyroid tumor cells from TR-beta(PV/PV) mice.We then took advantage of small molecule inhibitors targeting Akt, MEK, PI3K, Hsp90 or BRAF used in clinical trials for chemotherapy of solid tumors. As their toxicity profiles are well-accepted, if they increase thyroidal RAIU, they could be immediately employed in clinical trials to improve RAI treatment efficacy. We identified that PI3K inhibitor GDC-0941 outperformed other inhibitors in increasing TSH-stimulated RAIU in PCCl3 and BRAF(V600E)-expressing PCCl3 cells, by greatly decreasing iodide efflux rate. Alarmingly, TGF-beta dramatically reduced RAIU even upon treatment with inhibitors. Apigenin counteracted the RAIU reduction by TGF-beta by increasing NIS protein. Taken together, co-treatment of GDC-0941 with Apigenin may increase therapeutic efficacy of RAI in invasive fronts of thyroid cancer. While much is known about signaling nodes, little is known about microRNAs (miRs) regulating NIS and RAIU. We identified that miR-339-5p decreased endogenous NIS mRNA and RAIU in MCF-7 human breast cancer cells and in PCCl3 cells. Among 38 miRs deregulated by TGF-beta, Akti-1/2 or 17-AAG in PCCl3 cells, 18 were conserved in humans. One of the 18 miRs, miR-195, was predicted to bind to hNIS-3’UTR and its overexpression decreased hNIS-mediated RAIU in MCF-7 cells. MiR-339-5p was modestly increased, yet miR-195 was significantly decreased in PTCs. Expression profiles of the 18 miRs were able to separate most PTCs from non-malignant thyroid tissues. Taken together, we hope that these studies would serve as valuable tools to develop novel strategies for optimal use of RAI in clinical management of thyroid cancer. 2015-05-27 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914 http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.

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