title: Modulation of thyroidal radioiodide uptake by oncological pipeline inhibitors and Apigenin.
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.
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH-43210, USA.|Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH-43210, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Lakshmanan
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH-43210, USA.|Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH-43210, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Scarberry
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH-43210, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Green
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH-43210, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Centre de Recherche en Cancérologie de LYON (CRCL)-UMR 1052-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de LYON, F-69372, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Selmi-Ruby
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH-43210, USA.|Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH-43210, USA.|Comprehensive Cancer Center, The Ohio State University, Columbus, OH-43210, USA.
authors.forename: Sissy M
authors.initials: SM
authors.lastname: Jhiang
mesh_terms: D000818:Animals; D047310:Apigenin / Q000494:pharmacology*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D007124:Immunoenzyme Techniques; D007457:Iodine Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011877:Radionuclide Imaging; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013961:Thyroid Gland / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D016212:Transforming Growth Factor beta; D047310:Apigenin; D051096:Proto-Oncogene Proteins c-ret; C495001:Ret protein, rat
keywords: GDC-0941; NIS; TGF-β; apigenin; thyroid cancer