Regulation of Sodium Iodide Symporter Gene Expression by Rac1/p38β Mitogen-activated Protein Kinase Signaling Pathway in MCF-7 Breast Cancer Cells
Regulation of Sodium Iodide Symporter Gene Expression by Rac1/p38β Mitogen-activated Protein Kinase Signaling Pathway in MCF-7 Breast Cancer Cells
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DOI：
10.1074/jbc.m111.315523
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发表时间：
2012-01-27
影响因子：
4.8
通讯作者：
Brent, Gregory A.
中科院分区：
文献类型：
--
作者：
Kogai, Takahiko;Liu, Yan-Yun;Brent, Gregory A.
P38MAPK的激活是乳腺癌和甲状腺细胞增殖和分化的关键途径。钠/碘同向转运体(NIS)在甲状腺和哺乳期乳房浓缩碘。全反式维甲酸(Tra)显著诱导某些乳腺癌细胞株的NIS活性，并促进摄取足以达到靶向细胞毒作用的β-放射性碘I-131。为了确定选择性刺激NIS表达的信号转导途径，我们研究了MCF-7乳腺癌细胞中rac1-p38信号通路的调控，并将其与FRTL-5大鼠甲状腺细胞中的调控进行了比较。用药物抑制剂和小干扰RNA进行的功能丧失实验以及p38亚型的RT-PCR分析表明，在MCF-7细胞中充分表达NIS需要rac1、MAPK 3B和p38β的存在。相反，p38α对FRTL-5细胞中NIS的表达至关重要。用反式或过表达rac1处理诱导了p38亚型的磷酸化，包括p38β。在MCF-7细胞中，一个显性的Rac1负性突变体可阻断反式激活蛋白诱导的磷酸化。过表达p38β或rac1显著增强反式刺激的MCF-7细胞中NIS的表达(分别为1.9倍和3.9倍)。这项研究表明，乳腺癌细胞和甲状腺细胞中不同的p38亚型对NIS有不同的调节作用。靶向p38的异构体选择性激活可以增强NIS的诱导，导致I-131浓度的更高疗效和对乳腺癌的治疗。
Activation of p38 MAPK is a key pathway for cell proliferation and differentiation in breast cancer and thyroid cells. The sodium/iodide symporter (NIS) concentrates iodide in the thyroid and lactating breast. All-trans-retinoic acid (tRA) markedly induces NIS activity in some breast cancer cell lines and promotes uptake of beta-emitting radioiodide I-131 sufficient for targeted cytotoxicity. To identify a signal transduction pathway that selectively stimulates NIS expression, we investigated regulation by the Rac1-p38 signaling pathway in MCF-7 breast cancer cells and compared it with regulation in FRTL-5 rat thyroid cells. Loss of function experiments with pharmacologic inhibitors and small interfering RNA, as well as RT-PCR analysis of p38 isoforms, demonstrated the requirement of Rac1, MAPK kinase 3B, and p38 beta for the full expression of NIS in MCF-7 cells. In contrast, p38 alpha was critical for NIS expression in FRTL-5 cells. Treatment with tRA or overexpression of Rac1 induced the phosphorylation of p38 isoforms, including p38 beta. A dominant negative mutant of Rac1 abolished tRA-induced phosphorylation in MCF-7 cells. Overexpression of p38 beta or Rac1 significantly enhanced (1.9- and 3.9-fold, respectively), the tRA-stimulated NIS expression in MCF-7 cells. This study demonstrates differential regulation of NIS by distinct p38 isoforms in breast cancer cells and thyroid cells. Targeting isoform-selective activation of p38 may enhance NIS induction, resulting in higher efficacy of I-131 concentration and treatment of breast cancer.