MAPK pathway inhibitors enhance radioiodine sensitivity in anaplastic thyroid carcinoma through promoting NIS expression and ARF4-mediated NIS membrane transport

Anaplastic thyroid cancer (ATC) patient develops resistance to radioactive iodine (RAI) due to diminished sodium-iodide symporter (NIS) expression and mislocalization to the cell membrane. MAPK pathway inhibitors have demonstrated efficacy in enhancing RAI avidity in radioiodine-refractory papillary thyroid carcinoma and ATC. Elucidating this mechanism may lead to novel therapeutic approaches for ATC treatment. The cytotoxic effects of three MAPK pathway inhibitors (selumetinib, vemurafenib, dabrafenib) were assessed in ATC cell lines and xenograft models via viability assays and 18 F-FDG PET/CT. We investigated their impact on radioiodine metabolism by analyzing the expression of key genes (NIS, TSHR, and TPO) and trafficking regulators (ARF4, PIGU, and β-catenin) via Western blotting, and assessing NIS localization and function through immunofluorescence and uptake assays. The protein interaction between NIS and ARF4 was examined via co-immunoprecipitation (co-IP) and immunofluorescence. MAPK pathway inhibitors reduced the viability of ATC cell lines. ATC cells exhibited restored iodine metabolism-related gene expression after treatment, and pronounced increases in membrane-localized NIS were detected via the promotion of ARF4 expression. Furthermore, MAPK pathway inhibitors increased radioiodine uptake in ATC cells. The MAPK pathway inhibitors enhance NIS function through two mechanisms: upregulation of NIS expression and increased ARF4-mediated NIS membrane transport.