Iodide- and Glucose-Handling Gene Expression Regulated by Sorafenib or Cabozantinib in Papillary Thyroid Cancer
Iodide- and Glucose-Handling Gene Expression Regulated by Sorafenib or Cabozantinib in Papillary Thyroid Cancer
复制标题
索拉非尼或卡博替尼在甲状腺乳头状癌中调节碘化物和葡萄糖处理基因的表达
DOI：
10.1210/jc.2014-3023
复制
发表时间：
2015-05-01
影响因子：
5.8
通讯作者：
Chen, Libo
中科院分区：
文献类型：
--
作者：
Ruan, Maomei;Liu, Min;Chen, Libo
内容：碘处理基因的异常沉默伴随着葡萄糖代谢的上调是甲状腺乳头状癌（PTC）放射性碘治疗的主要挑战。目的：本研究旨在评估酪氨酸激酶抑制剂对携带RET/PTC 1重排的BHP 2-7细胞中碘处理和葡萄糖处理基因表达的影响。主要结果指标：在该体外研究中，分别通过细胞增殖测定、细胞周期分析和膜联蛋白V-FITC凋亡测定来研究索拉非尼或卡博替尼对细胞生长、周期和凋亡的影响。使用Western印迹评价两种试剂对信号转导途径的影响。定量实时PCR，Western印迹，免疫荧光，放射性同位素摄取测定被用来评估碘处理和葡萄糖处理基因expression.Results：这两种化合物抑制细胞增殖的时间依赖性和剂量依赖性的方式，并导致细胞周期停滞在G 0/G1期。索拉非尼阻断RET、AKT和ERK 1/2磷酸化，而卡博替尼阻断RET和AKT磷酸化。任何一种药物都可以诱导碘处理基因表达的恢复和葡萄糖转运蛋白1和3表达的抑制。证实了由任一药剂诱导的钠/碘同向转运体的稳健表达，并且I-125摄取相应地增强。F-18-氟脱氧葡萄糖的积累显着降低治疗后，无论是索拉非尼或cabozantinib.Conclusions：索拉非尼和cabozantinib有显着的影响，细胞增殖，细胞周期阻滞，信号转导通路在PTC细胞窝藏RET/PTC 1重排。这两种药物都有可能用于增强碘处理基因的表达和抑制葡萄糖转运蛋白基因的表达。
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 I-125 uptake was correspondingly enhanced. F-18-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.