The sodium iodide symporter (NIS): regulation and approaches to targeting for cancer therapeutics

Abstract

Expression of the sodium iodide symporter (NIS) is required for efficient iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, β-emitting radioactive iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioiodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of iodide uptake is required to target tumors with radioiodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioiodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioiodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS.

Fig. 1

Schematic representation of iodide transport in the thyroid gland. The thyroid gland consist of follicles with one layer of epithelial cells surrounding the lumen. Iodide (I⁻) in circulation is transported into the lumen via basolateral NIS and apical pendrin. The activity of NIS requires the Na⁺-gradient maintained by Na⁺-K⁺ ATPase. Iodide in the lumen is organified with Tg by TPO in the presence of H₂O₂ produced mainly by DUOX2. The iodinated tyrosine residues are used for synthesis of thyroid hormones, triiodothyronine (T₃) or thyroxine (T₄).

Fig. 2

A simplified model of the free iodide cycle in the human body. Most iodine is ingested as iodide (I⁻) or iodate (IO₃⁻), which is rapidly reduced to iodide (Burgi et al., 2001). Iodide is absorbed by small intestine via the apical NIS, transferred into the circulation, and then taken up in the thyroid gland, as well as lactating breast, although ~90% of ingested iodide will be excreted by the kidneys. A fraction of circulating iodide is released again to the gastrointestinal tract through the salivary glands and stomach that express basolateral NIS. The sodium-dependent multivitamin transporter (SLC5A6) has also been proposed to mediate sodium-coupled iodide transport in the intestines (de Carvalho & Quick, 2011). OT, oxytocin; PRL, prolactin.

Fig. 3

Regulation of the NUE in thyroid cells. A. Map of the human chromosome 19p around the NIS gene locus. The “A” in the translation start site (ATG) of NIS is referred to as +1. B. TSHR signaling pathways to NUE. NIS expression in thyroid cells is predominantly regulated by the TSHR signaling to NUE. Gain-of-function studies of the molecules, indicated by red color, have demonstrated stimulation of the NUE activity. The consensus sequences of cis-elements of PAX8, CRE, and USF1 are indicated along with the sequence of human NUE. *, Stimulatory effects have been reported with rat NUE, which contains an additional Pax8 element and an NFκB element (Nicola et al., 2010). AC, adenylyl cyclase; Ref-1, apurinic apyrimidinic endonuclease redox effector factor-1.

Fig. 4

Differential mechanisms of NIS up-regulation by PI3K inhibition with LY294002 in rat thyroid cells and BHP 2–7 papillary thyroid cancer cells. *, LY294002 induces Pax8 in PCCL3 cells, but not in FRTL-5 cells, resulting in a more robust induction of NIS in PCCL3 cells (Kogai et al., 2008b).

Fig. 5

Effects of retinoid receptor agonists on iodide uptake in MCF-7 cells in vitro. Cells were treated with 10⁻⁶ M of each agonist for 48 hours, and iodide uptake assay was performed with 20 mCi/mmol of Na¹²⁵I, as described (Kogai et al., 2008b; Weiss et al., 1984). The uptake was normalized by cellular protein amount or cell number. Fold-induction over the group without retinoid treatment is presented. *, P < 0.02; ** P < 0.01, when compared to the negative control (n = 3 or 4).

Fig. 6

Comparison of genomic and non-genomic effects of RA. Conversion of isomers of RA is also indicated. The RAR/RXR heterodimer, not bound to chromatin contributes to kinase cascade activation, whereas the RAR/RXR bound to an RARE (retinoic acid response element) regulates expression of the target gene. Retinoic acids are hydrophobic compounds and associate with soluble retinoid-binding proteins (not shown in this schema) in the intracellular as well as extracellular compartments.

Fig. 7

Distinct p38 pathways regulate NIS expression in FRTL-5 rat thyroid cells and MCF-7 breast cancer cells. CHOP, CCAAT/enhancer-binding protein-homologous protein. This figure is reproduced from (Kogai et al., 2012).