The Sodium Iodide Symporter and Its Potential Role in Cancer Therapy

TLDR: After NIS was cloned, several studies in FRTL-5 cells and cultured human thyroid cells showed that treatment with TSH stimulates iodide transport activity as well as NIS gene and protein expression, suggesting that TSH regulates NIS expression through the cAMP signal transduction pathway.

Abstract: Active transport of iodide into the thyroid gland is a crucial and rate-limiting step in the biosynthesis of thyroid hormones that play an important role in the metabolism, growth, and maturation of a variety of organ systems, in particular the nervous system (1) Although it has been known for decades that iodide transport into the thyroid gland is mediated by a specific sodium-dependent iodide transporter located at the basolateral membrane of thyroid follicular cells, the sodium iodide symporter (NIS) gene was cloned just 4 yr ago (2, 3) After cloning of the rat sodium iodide symporter (rNIS) from a Fisher rat thyroid line (FRTL-5)derived complementary DNA (cDNA) library (2), the human sodium iodide symporter (hNIS) was cloned from a human thyroid cDNA library in 1996 (3) The hNIS gene is localized on chromosome 19p12–132 and encodes a glycoprotein of 643 amino acids (aa) with a molecular mass of approximately 70–90 kDa The coding region of hNIS contains 15 exons interrupted by 14 introns and codes for a 39-kb messenger ribonucleic acid (mRNA) transcript (4) As a member of the sodium-dependent transporter family, NIS is an intrinsic membrane protein with 13 putative transmembrane domains, an extracellular amino-terminus, and an intracellular carboxyl-terminus The NIS protein has three potential Nlinked glycosylation sites; 1 is located in the fourth extracellular (seventh extramembranous domain), and 2 are located in the last extracellular (13th extramembranous domain) loop (5) (Fig 1) NIS cotransports two sodium ions along with one iodide ion, with the transmembrane sodium gradient serving as the driving force for iodide uptake The sodium gradient providing the energy for this transfer is generated by the ouabain-sensitive Na/K-adenosine triphosphatase (Na/ K-ATPase) NIS-mediated iodide transport is, therefore, inhibited by the Na/K-ATPase inhibitor ouabain as well as by the competitive inhibitors thiocyanate and perchlorate (1) (Fig 2) After active transport across the basolateral membrane of thyroid follicular cells, iodide is translocated across the apical membrane by pendrin, the Pendred syndrome gene product, which is a chloride/iodide transporter (6–10) (Fig 2) Other apical anion transporters may also be involved At the cell/colloid interface iodide is organified in a complex reaction involving oxidation catalyzed by thyroid peroxidase (TPO) and incorporation into tyrosyl residues along the thyroglobulin (Tg) backbone The thyroid hormones T3 and T4 are synthesized by coupling of two iodotyrosine residues and are stored in the colloid (Fig 2) The iodide organification step can be inhibited by propylthiouracil and methimazole, which are TPO enzyme inhibitors All of these steps are stimulated through pituitary-derived TSH, which interacts with the TSH receptor at the basolateral membrane of thyroidal cells (1) It has been known for many years that TSH stimulates iodide transport into the thyroid gland via the adenylate cyclase-cAMP pathway (1) After NIS was cloned, several studies in FRTL-5 cells and cultured human thyroid cells showed that treatment with TSH stimulates iodide transport activity as well as NIS gene and protein expression (11, 12) Forskolin and dibutyryl cAMP are able to mimic this stimulatory effect on both iodide transport activity as well as NIS gene and protein expression, suggesting that TSH regulates NIS expression through the cAMP signal transduction pathway (11) (Fig 2) In addition to its key role in thyroid physiology, NISmediated iodide accumulation in the thyroid gland is a crucial prerequisite for diagnostic scintigraphic imaging as well as for the highly efficient radioiodine therapy of benign and malignant thyroid diseases The purpose of this review is to summarize and discuss the current knowledge of NIS and its diagnostic and therapeutic implications in thyroidal and nonthyroidal cancer