Protein Synthesis Inhibitors Induce the Sodium/Iodide Symporter Expression in Various Human Cancer Cells

Abstract

Radioiodide treatment is often carried out for complete ablation of residual and/or recurrent tumors after total thyroidectomy. Since radioiodide is actively accumulated via the sodium/iodide symporter (NIS), enhancement of its expression is critical to target cancer cells with radioiodide. To investigate if protein synthesis inhibitors induced endogenous NIS expression in human cancer cells, we evaluated the effects of translation inhibitors, cycloheximide (CHX) and homoharringtonine (HHT), on the NIS expression in MCF-7 breast cancer cells, MKN45 gastric cancer cells, and BHP 2-7 papillary thyroid cancer cells. CHX significantly upregulated NIS mRNA expression in MCF-7 cells (up to -397-fold; EC₅₀, -4.9 μg/mL), as well as MKN45 cells (up to 82-fold; EC₅₀, 43.8 μg/mL), but not BHP 2-7 cells. Iodide uptake was also significantly increased (-1.7-fold) in MCF-7 cells. HHT, an anti-leukemic agent, induced NIS expression in MCF-7 cells (up to -38-fold; EC₅₀, 24.6 ng/mL), MKN45 cells (-9-fold; EC₅₀, 256 ng/mL), and BHP 2-7 cells (-100 fold; EC₅₀, 767 ng/mL). The induction of NIS by CHX in MCF-7 cells, as well as that by HHT in MKN45 cells, were susceptible to p38 MAPK inhibition. To our knowledge, this is the first report demonstrating the induction of NIS by protein synthesis inhibitors in human cancer cells. Further elucidation would uncover more specific, and thus less toxic molecular targets for the enhancement of NIS expression, expecting radioiodide therapy with higher efficacy and safety.