Mitogen-activated protein kinase signaling enhances sodium iodide symporter function and efficacy of radioiodide therapy in nonthyroidal cancer cells.
Although the success of sodium/iodide symporter (NIS) gene-based 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)I-mediated 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. Biotinylation-immunoblotting 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.


CONCLUSIONS
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.
Jung
Kyung-Ho
KH
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Paik
Jin-Young
JY
Ko
Bong-Ho
BH
Lee
Kyung-Han
KH
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects*; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage*; D020935:MAP Kinase Signaling System / Q000528:radiation effects*; D016716:PC12 Cells; D019275:Radiopharmaceuticals / Q000008:administration & dosage; D051381:Rats; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D000099209:Sodium-Iodide Symporters
D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D027981:Symporters; D000099209:Sodium-Iodide Symporters