Mitogen-Activated Protein Kinase Signaling Enhances Sodium Iodide Symporter Function and Efficacy of Radioiodide Therapy in Nonthyroidal Cancer Cells

Abstract

Although the success of sodium/iodide symporter (NIS) genebased cancer therapy is critically dependent on the level of radioiodide accumulation attained, recent evidence indicates that successful therapy relies not solely on NIS amount but also crucially on its functional activity. In this study, we investigated the role of kinase-linked signaling on the regulation of NIS function in cancer cells. Methods: T47D human breast cancer and PC-12 rat pheochromocytoma cells were transduced with the human NIS genes via an adenoviral vector. Cells were measured for 125 I uptake, and the effects of activation or inhibition of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase pathways were evaluated. Membrane localization of NIS was evaluated by biotinylation-immunoblotting and confocal microscopy. 131 Imediated cancer cell killing was evaluated by clonogenic assays. Results: NIS function was acutely reduced by short stimulation with the PKC activator phorbol 12-myristate 13-acetate and increased by its inhibition with staurosporine or prolonged phorbol 12-myristate 13-acetate exposure. Surprisingly, epidermal growth factor (EGF) caused a strong dose-dependent augmentation of radioiodide transport, accompanied by extracellular signal-regulated kinase (ERK)-1/2 activation. Both effects were completely abrogated by specific MAP kinase kinase (MEK) inhibitors, which also reduced basal NIS function. Hence, radioiodide uptake levels could differ 24-fold, depending on ERK activity. Biotinylationimmunoblotting and confocal microscopy revealed that EGF increases plasma membrane-localized NIS without affecting total cellular levels. EGF stimulation was sufficient to enhance the killing effect of 131 I on the cancer cells. Conclusion: Thus, PKC and ERK signaling play important roles in the regulation of NIS function, and control of these signaling pathways may help enhance the efficacy of radioiodide cancer therapy.

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

“…Treatment with epidermal growth factor increased iodide uptake in NIS -transfected T47D human breast cancer cells, as well as PC12 rat pheochromocytoma cells. This effect was abolished by PD98059 (Jung et al, 2008), a MEK-1 inhibitor, indicating a role of the MEK-ERK signaling cascade in the NIS translocation.…”

“…The NIS translocation to the cell surface membrane is enhanced by EGF (epidermal growth factor) receptor stimulation in NIS -introduced non-thyroidal cancer cells (Jung et al, 2008). Treatment with epidermal growth factor increased iodide uptake in NIS -transfected T47D human breast cancer cells, as well as PC12 rat pheochromocytoma cells.…”

Sodium iodide symporter (NIS) in extrathyroidal malignancies: focus on breast and urological cancer

“…It may take advantage of the enormous progress obtained in thyroid cancer field of research in the elucidation of the molecular mechanism that controls thyrocyte differentiation and, in particular, NIS expression. For example, inhibitors of signal transduction pathways, as PI3K/AKT inhibitors and MEK/ERK inhibitors, or HDAC inhibitors, have demonstrated the ability to enhance the functional NIS expression in some thyroid cancer, as well as non-thyroid cancer cells [85,117,118] and, very recently, a clinical pilot study has actually demonstrated the effectiveness of the MEK inhibitor selumetinib to increase radioiodide uptake in a number of patients with advanced thyroid cancer [114]. …”

Flavonoids, Thyroid Iodide Uptake and Thyroid Cancer—A Review

“…Besides increasing the intracellular levels of cAMP, TSH can also act by activating other intracellular pathways, such as ERK-MEK and p38MAPK [46]. However, the actual importance of these pathways as modulators of the expression and activity of NIS is still controversial [46,47,48]. NIS expression and function can also be modulated by pathways activated by insulin and IGF-1 [49,50].…”