title: Iodide- and glucose-handling gene expression regulated by sorafenib or cabozantinib in papillary thyroid cancer.
abstract: BACKGROUND
  The aberrant silencing of iodide-handling genes accompanied by up-regulation of glucose metabolism presents a major challenge for radioiodine treatment of papillary thyroid cancer (PTC).
  
  
  OBJECTIVE
  This study aimed to evaluate the effect of tyrosine kinase inhibitors on iodide-handling and glucose-handling gene expression in BHP 2-7 cells harboring RET/PTC1 rearrangement.
  
  
  METHODS
  In this in vitro study, the effects of sorafenib or cabozantinib on cell growth, cycles, and apoptosis were investigated by cell proliferation assay, cell cycle analysis, and Annexin V-FITC apoptosis assay, respectively. The effect of both agents on signal transduction pathways was evaluated using the Western blot. Quantitative real-time PCR, Western blot, immunofluorescence, and radioisotope uptake assays were used to assess iodide-handling and glucose-handling gene expression.
  
  
  RESULTS
  Both compounds inhibited cell proliferation in a time-dependent and dose-dependent manner and caused cell cycle arrest in the G0/G1 phase. Sorafenib blocked RET, AKT, and ERK1/2 phosphorylation, whereas cabozantinib blocked RET and AKT phosphorylation. The restoration of iodide-handling gene expression and inhibition of glucose transporter 1 and 3 expression could be induced by either drug. The robust expression of sodium/iodide symporter induced by either agent was confirmed, and (125)I uptake was correspondingly enhanced. (18)F-fluorodeoxyglucose accumulation was significantly decreased after treatment by either sorafenib or cabozantinib.
  
  
  CONCLUSIONS
  Sorafenib and cabozantinib had marked effects on cell proliferation, cell cycle arrest, and signal transduction pathways in PTC cells harboring RET/PTC1 rearrangement. Both agents could be potentially used to enhance the expression of iodide-handling genes and inhibit the expression of glucose transporter genes.
authors.affiliation: Department of Nuclear Medicine (M.R., M.L., L.C.), Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; and Section of Cancer Stem Cells (Q.D.), Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200032, China.
authors.forename: Maomei
authors.initials: M
authors.lastname: Ruan
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Qianggang
authors.initials: Q
authors.lastname: Dong
authors.forename: Libo
authors.initials: L
authors.lastname: Chen
mesh_terms: D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001324:Autoantigens / Q000235:genetics; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051272:Glucose Transporter Type 1 / Q000235:genetics; D051274:Glucose Transporter Type 3 / Q000235:genetics; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics; D033862:Iron-Binding Proteins / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011989:Receptors, Thyrotropin / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077157:Sorafenib; D027981:Symporters / Q000235:genetics; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000099209:Sodium-Iodide Symporters
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001324:Autoantigens; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D007453:Iodide Peroxidase; D033862:Iron-Binding Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051096:Proto-Oncogene Proteins c-ret; D011725:Pyridines; D011989:Receptors, Thyrotropin; D000077157:Sorafenib; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C051615:transgelin; C558660:cabozantinib; C056658:TPO protein, human; C099282:RET protein, human