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Linking loss of sodium-iodide symporter expression to DNA damage

Journal article
Authors Madeleine Nordén Lyckesvärd
Nirmal Kapoor
Camilla Ingeson-Carlsson
Therese Carlsson
Jan-Olof Karlsson
Per Postgård
Jakob Himmelman
Eva Forssell-Aronsson
Ola Hammarsten
Mikael Nilsson
Published in Experimental Cell Research
Volume 344
Issue 1
Pages 120-131
ISSN 0014-4827
Publication year 2016
Published at Institute of Clinical Sciences, Department of Radiation Physics
Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 120-131
Language en
Links dx.doi.org/10.1016/j.yexcr.2016.04....
Keywords Sodium iodide symporter, DNA damage response, ATM, Radioiodine, Calicheamicin, Thyroid cancer, double-strand breaks, messenger-rna expression, thyroid, epithelial-cells, sodium/iodide symporter, hydrogen-peroxide, atm, kinase, posttranscriptional regulation, differentiated cells, ionizing-radiation, oxidative stress, Oncology, Cell Biology
Subject categories Cell biology, Cancer and Oncology

Abstract

Radiotherapy of thyroid cancer with I-131 is abrogated by inherent loss of radioiodine uptake due to loss of sodium iodide symporter (NIS) expression in poorly differentiated tumor cells. It is also known that ionizing radiation per se down-regulates NIS (the stunning effect), but the mechanism is unknown. Here we investigated whether loss of NIS-mediated iodide transport may be elicited by DNA damage. Calicheamicin, a fungal toxin that specifically cleaves double-stranded DNA, induced a full scale DNA damage response mediated by the ataxia-telangiectasia mutated (ATM) kinase in quiescent normal thyrocytes. At sublethal concentrations (< 1 nM) calicheamicin blocked NIS mRNA expression and transepithelial iodide transport as stimulated by thyrotropin; loss of function occurred at a much faster rate than after I-131 irradiation. KU-55933, a selective ATM kinase inhibitor, partly rescued NIS expression and iodide transport in DNA-damaged cells. Prolonged ATM inhibition in healthy cells also repressed NIS-mediated iodide transport. ATM-dependent loss of iodide transport was counteracted by IGF-1. Together, these findings indicate that NIS, the major iodide transporter of the thyroid gland, is susceptible to DNA damage involving ATM-mediated mechanisms. This uncovers novel means of poor radioiodine uptake in thyroid cells subjected to extrinsic or intrinsic genotoxic stress. (C) 2016 Elsevier Inc. All rights reserved.

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