Oncotarget

Research Papers:

Modulation of thyroidal radioiodide uptake by oncological pipeline inhibitors and Apigenin

Aparna Lakshmanan, Daniel Scarberry, Jill A. Green, Xiaoli Zhang, Samia Selmi-Ruby and Sissy M. Jhiang _

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Oncotarget. 2015; 6:31792-31804. https://doi.org/10.18632/oncotarget.5172

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Abstract

Aparna Lakshmanan1,2, Daniel Scarberry1,2, Jill A. Green3, Xiaoli Zhang4, Samia Selmi-Ruby5, Sissy M. Jhiang1,2,3

1Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH-43210, USA

2Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH-43210, USA

3Comprehensive Cancer Center, The Ohio State University, Columbus, OH-43210, USA

4Center for Biostatistics, The Ohio State University, Columbus, OH-43210, USA

5Centre de Recherche en Cancérologie de Lyon – UMR 1052- INSERM (Institut National de la Santé et de la Recherche Médicale, INSERM, Faculté de Médecine RTH Laennec, F-69372 Lyon, France

Correspondence to:

Sissy M. Jhiang, e-mail: jhiang.1@osu.edu

Keywords: thyroid cancer, NIS, TGF-β, apigenin, GDC-0941

Received: June 02, 2015     Accepted: August 27, 2015     Published: September 09, 2015

ABSTRACT

Targeted radioiodine therapy for thyroid cancer is based on selective stimulation of Na+/I- Symporter (NIS)-mediated radioactive iodide uptake (RAIU) in thyroid cells by thyrotropin. Patients with advanced thyroid cancer do not benefit from radioiodine therapy due to reduced or absent NIS expression. To identify inhibitors that can be readily translated into clinical care, we examined oncological pipeline inhibitors targeting Akt, MEK, PI3K, Hsp90 or BRAF in their ability to increase RAIU in thyroid cells expressing BRAFV600E or RET/PTC3 oncogene. Our data showed that (1) PI3K inhibitor GDC-0941 outperformed other inhibitors in RAIU increase mainly by decreasing iodide efflux rate to a great extent; (2) RAIU increase by all inhibitors was extensively reduced by TGF-β, a cytokine secreted in the invasive fronts of thyroid cancers; (3) RAIU reduction by TGF-β was mainly mediated by NIS reduction and could be reversed by Apigenin, a plant-derived flavonoid; and (4) In the presence of TGF-β, GDC-0941 with Apigenin co-treatment had the highest RAIU level in both BRAFV600E expressing cells and RET/PTC3 expressing cells. Taken together, Apigenin may serve as a dietary supplement along with small molecule inhibitors to improve radioiodine therapeutic efficacy on invasive tumor margins thereby minimizing future metastatic events.


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