Enhancing functional sodium iodine symporter by regulation of glycosylation improves radioiodine therapy

Objectives The depletion of sodium iodide symporter (NIS) gene expression in some thyroid cancer patients has been known as a significant factor to limit the efficacy of radioactive iodine therapy. In this study, we investigated the functional NIS by glycosylation using molecular imaging.

Methods HeLa cells were stably transfected with NIS-tdTomato fusion gene (HeLa/NIS-Tom). HeLa/NIS-Tom cells were treated with Tunicamycin to inhibit glycosylation and cAMP to increase glycosylation. Immunohistochemistry and western blotting was performed to determine the NIS expression. The regulated functional NIS in HeLa/NIS-Tom cells was estimated by radioiodine uptake and glycosylation analysis kit. NIS expression of tumor xenograft and its activity was estimated by fluorescence and Tc-99m scintigraphic imaging.

Results Glycosylated levels of NIS protein of HeLa/NIS-Tom cells with Tunicamycin were decreased by 0.57 fold and radioiodine uptake was also decreased by 0.29 fold. In contrast, cAMP treated HeLa/NIS-Tom cells revealed increased glycosylated NIS protein levels by 1.99 fold and radioiodine uptake levels were increased by 4.12 fold. In mice model, cAMP treated tumor xenograft showed 4.15 fold higher fluorescent signals and increased Tc-99m uptake as well.

Conclusions We demonstrated that the functional NIS is closely related to the regulation of glycosylation of NIS. Our results indicate that the enhancement of functional NIS protein using cAMP is applicable to not only the patients who are irresponsible to radioiodine therapy, but also curable patients who simply need a lower dosage of radioiodine therapy