Activation of the PI3 kinase pathway by retinoic acid mediates sodium/iodide symporter induction and iodide transport in MCF-7 breast cancer cells.
Activation of the PI3 kinase pathway by retinoic acid mediates sodium/iodide symporter induction and iodide transport in MCF-7 breast cancer cells.
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DOI：
10.1158/0008-5472.can-08-3234
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发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Brent GA
中科院分区：
文献类型：
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作者：
Ohashi E;Kogai T;Kagechika H;Brent GA
甲状腺和乳腺中的碘摄取由钠/碘同向转运体（NIS）介导。NIS激活用于甲状腺癌的放射性碘成像和治疗消融。NIS在超过70%的乳腺癌中表达，但其水平不足以进行放射性碘治疗。全反式维甲酸（tRA）诱导NIS基因表达和功能性碘摄取在人乳腺癌细胞系和小鼠乳腺癌模型。tRA通常通过视黄酸受体（RAR）与靶基因的直接相互作用来调节基因表达，但它也可以通过非基因组途径起作用。我们报告了tRA治疗对PI 3 K信号转导途径的直接影响，该途径介导了tRA诱导的MCF-7乳腺癌细胞中的NIS表达。MCF-7细胞表达所有三种RAR亚型α、β和γ以及RXRα。我们以前发现RARβ和RXRα对tRA诱导NIS很重要。用PI 3 K抑制剂LY 294002或用siRNA“敲低”p85α处理，可消除tRA诱导的NIS表达。免疫沉淀实验和GST pull-down实验证实RARβ2、RXRα和p85α之间存在直接的相互作用。RA还诱导MCF-7细胞Akt的快速激活。用Akt抑制剂或用siRNA“敲低”Akt的处理降低NIS表达。这些发现表明，RA诱导的NIS在MCF-7细胞中是由PI 3 K途径的快速激活介导的，并涉及与RAR和RXR的直接相互作用。明确这些机制将有助于进一步增强NIS表达的方法，以及影响乳腺癌生长和分化的类维生素A靶点。
Iodide uptake in the thyroid and breast is mediated by the sodium/iodide symporter (NIS). NIS activation is utilized for radioiodide imaging and therapeutic ablation of thyroid carcinoma. NIS is expressed in more than 70% of breast cancers, but at a level insufficient for radioiodine treatment. All-trans retinoic acid (tRA) induces NIS gene expression and functional iodide uptake in human breast cancer cell lines and mouse breast cancer models. tRA usually regulates gene expression by direct interaction of Retinoic Acid Receptor (RAR) with a target gene, but it can also acts through nongenomic pathways. We report a direct influence of tRA treatment on the PI3K signal transduction pathway that mediates tRA-induced NIS expression in MCF-7 breast cancer cells. MCF-7 cells express all three RAR isoforms, α, β and γ, and RXRα. We previously identified RARβ and RXRα as important for NIS induction by tRA. Treatment with LY294002, the PI3K inhibitor, or p85α “knockdown” with siRNA, abolished tRA-induced NIS expression. Immunoprecipitation experiments and GST pull-down assay demonstrated a direct interaction between RARβ2, RXRα and p85α. RA also induced rapid activation of Akt in MCF-7 cells. Treatment with an Akt inhibitor or Akt “knockdown” with siRNA, reduced NIS expression. These findings indicate that RA-induction of NIS in MCF-7 cells is mediated by rapid activation of the PI3K pathway and involves direct interaction with RAR and RXR. Defining these mechanisms should lead to methods to further enhance NIS expression, as well as retinoid targets that influence growth and differentiation of breast cancer.