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

Lakshmanan, Aparna
http://orcid.org/0000-0001-6969-2912
http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
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.
Sissy Jhiang, PhD (Advisor)
Michael Ostrowski, PhD (Committee Member)
Matthew Ringel, MD (Committee Member)
Balveen Kaur, PhD (Committee Member)
144 p.
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

Recommended Citations

Citations

  • Lakshmanan, A. (2015). Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914

    APA Style (7th edition)

  • Lakshmanan, Aparna. Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914.

    MLA Style (8th edition)

  • Lakshmanan, Aparna. "Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429407914

    Chicago Manual of Style (17th edition)

osu1429407914
417
© 2015, some rights reserved.Creative Commons License Modulation of Sodium Iodide Symporter-mediated Thyroidal Radioiodide Uptake by Small Molecule Inhibitors, Natural Plant-based Products and microRNAs by Aparna Lakshmanan is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.