title: Induction of sodium/iodide symporter (NIS) expression and radioiodine uptake in non-thyroid cancer cells.
abstract: BACKGROUND
  This study was designed to explore the therapeutic potential of suppressing MAP kinase and PI3K/Akt pathways and histone deacetylase (HDAC) to induce the expression of sodium/iodide symporter (NIS) and radioiodine uptake in non-thyroid cancer cells.
  
  
  METHODS
  We tested the effects of the MEK inhibitor RDEA119, the Akt inhibitor perifosine, and the HDAC inhibitor SAHA on NIS expression in thirteen human cancer cell lines derived from melanoma, hepatic carcinoma, gastric carcinoma, colon carcinoma, breast carcinoma, and brain cancers. We also examined radioiodine uptake and histone acetylation at the NIS promoter in selected cells.
  
  
  RESULTS
  Overall, the three inhibitors could induce NIS expression, to various extents, in melanoma and all the epithelial carcinoma-derived cells but not in brain cancer-derived cells. SAHA was most effective and its effect could be significantly enhanced by RDEA119 and perifosine. The expression of NIS, at both mRNA and protein levels, was most robust in the melanoma cell M14, hepatic carcinoma cell HepG2, and the gastric carcinoma cell MKN-7 cell. Radioiodine uptake was correspondingly induced, accompanied by robust increase in histone acetylation at the NIS promoter, in these cells when treated with the three inhibitors.
  
  
  CONCLUSIONS
  This is the first demonstration that simultaneously suppressing the MAP kinase and PI3K/Akt pathways and HDAC could induce robust NIS expression and radioiodine uptake in certain non-thyroid human cancer cells, providing novel therapeutic implications for adjunct radioiodine treatment of these cancers.
authors.affiliation: Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Xing
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000493:pharmacokinetics; D027981:Symporters / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects*; D000077337:Vorinostat; D000099209:Sodium-Iodide Symporters
chemical_list: D004159:Diphenylamine; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007457:Iodine Radioisotopes; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D010767:Phosphorylcholine; D013449:Sulfonamides; D027981:Symporters; D000077337:Vorinostat; D000099209:Sodium-Iodide Symporters; C544830:N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; C105905:perifosine