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.
Highlights
Thyroid cancer incidence is rapidly increasing in the Unites States [1]
We show that PI3Ki GDC-0941 outperforms other inhibitors in further increasing TSHstimulated radioactive iodide (RAI) uptake (RAIU) in BRAFV600E expressing PCCl3 cells
We report that RAIU in the invasive fronts of thyroid cancer may be greatly reduced by TGF-β, even upon www.impactjournals.com/oncotarget treatment with the inhibitors that were shown to increase TSH-stimulated RAIU in the absence of TGF-β
Summary
Thyroid cancer incidence is rapidly increasing in the Unites States [1]. For thyroid cancer of poor prognosis, radioactive iodide (RAI) is administered for remnant ablation, and/or for targeted therapy of residual, recurrent, or metastatic cancer after total thyroidectomy. Targeted RAI therapy is facilitated by selective stimulation of Na+/ I- Symporter (NIS; SLC5A5)-mediated iodide uptake by thyrotropin (TSH) in thyroid cells. Patients with refractory or advanced thyroid cancer could not benefit from RAI targeted therapy due to absent or insufficient TSH-stimulated RAI uptake (RAIU). The BRAFV600E oncogene is the most common mutation found in thyroid cancer followed by the RET/ PTC rearrangements [2]. Pharmacological www.impactjournals.com/oncotarget inhibitors targeting BRAF/MEK [7, 8], PI3K/Akt [8,9,10] or Hsp90 [5] selectively increase RAIU in thyroid cell cultures and their modes of action have been summarized [11]. The effects of inhibitors for BRAF/ MEK [12] and Hsp90 [13] to increase RAIU have been validated in mouse models of thyroid cancer. A MEK inhibitor AZD6244 and a BRAFV600E inhibitor GSK2118436 were reported to further increase thyroidal RAI accumulation to an extent that may lead to clinical benefit in RAI-refractory patients in a Phase 2 clinical trial [14] and in a pilot study [15] respectively
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