Iodide- and Glucose-Handling Gene Expression Regulated by Sorafenib or Cabozantinib in Papillary Thyroid Cancer

• Published in: The journal of clinical endocrinology and metabolism 2015-05, Vol.100 (5), p.1771-1779
• Main Authors: Ruan, Maomei, Liu, Min, Dong, Qianggang, Chen, Libo
• Format: Article
• Language: English
• Subjects: Anilides - pharmacology; Anilides - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Autoantigens - genetics; Carcinoma, Papillary - drug therapy; Carcinoma, Papillary - genetics; Carcinoma, Papillary - pathology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 3 - genetics; Humans; Iodide Peroxidase - genetics; Iron-Binding Proteins - genetics; Microfilament Proteins - genetics; Muscle Proteins - genetics; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Niacinamide - therapeutic use; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-ret - genetics; Pyridines - pharmacology; Pyridines - therapeutic use; Receptors, Thyrotropin - genetics; Signal Transduction - drug effects; Signal Transduction - genetics; Symporters - genetics; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2014-3023

Context: 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. Main Outcome Measures: 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 125I uptake was correspondingly enhanced. 18F-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.