Transforming Growth Factor β/NR4A1-Inducible Breast Cancer Cell Migration and Epithelial-to-Mesenchymal Transition Is p38α (Mitogen-Activated Protein Kinase 14) Dependent
Transforming Growth Factor β/NR4A1-Inducible Breast Cancer Cell Migration and Epithelial-to-Mesenchymal Transition Is p38α (Mitogen-Activated Protein Kinase 14) Dependent
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DOI：
10.1128/mcb.00306-17
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发表时间：
2017-09-01
影响因子：
5.3
通讯作者：
Safe, Stephen
中科院分区：
文献类型：
--
作者：
Hedrick, Erik;Safe, Stephen
转化生长因子β（TGF-β）诱导的三脾阴性乳腺癌（TNBC）细胞迁移依赖于孤儿受体NR 4A 1的核输出，NR 4A 1在SMAD 7的蛋白酶体依赖性降解中发挥作用。在这项研究中，我们发现TGF-β诱导p38 α（促分裂原活化蛋白激酶14 [MAPK 14]），这反过来磷酸化NR 4A 1，导致受体的核输出。TGF-β/p38 α和NR 4A 1还在TNBC细胞中诱导上皮向间充质转化（EMT）和诱导β-连环蛋白中发挥重要作用，并且这些TGF-β诱导的反应和NR 4A 1的核输出被NR 4A 1拮抗剂、p38抑制剂SB 202190和p38 α的激酶死亡[p38（KD）]和显性阴性[p38（DN）]形式阻断。NR 4A 1核输出的抑制导致TGF-β诱导的β-连环蛋白的核输出，其随后经历蛋白酶体依赖性降解。TGF-β诱导的β-连环蛋白还通过在NR 4A 1启动子上形成β-连环蛋白-TCF-3/TCF-4/LEF-1复合物来调节NR 4A 1表达。因此，TNBC细胞中TGF-β诱导的NR 4A 1核输出在细胞迁移、SMAD 7降解、EMT和β-连环蛋白诱导中起重要作用，并且所有这些途径都被双吲哚衍生的NR 4A 1拮抗剂抑制，所述双吲哚衍生的NR 4A 1拮抗剂抑制受体的核输出，从而阻断TGF-β诱导的迁移和EMT。
Transforming growth factor beta (TGF-beta)-induced migration of triplenegative breast cancer (TNBC) cells is dependent on nuclear export of the orphan receptor NR4A1, which plays a role in proteasome-dependent degradation of SMAD7. In this study, we show that TGF-beta induces p38 alpha (mitogen-activated protein kinase 14 [MAPK14]), which in turn phosphorylates NR4A1, resulting in nuclear export of the receptor. TGF-beta/p38 alpha and NR4A1 also play essential roles in the induction of epithelial-to-mesenchymal transition (EMT) and induction of beta-catenin in TNBC cells, and these TGF-beta-induced responses and nuclear export of NR4A1 are blocked by NR4A1 antagonists, the p38 inhibitor SB202190, and kinase-dead [p38(KD)] and dominant-negative [p38(DN)] forms of p38 alpha. Inhibition of NR4A1 nuclear export results in nuclear export of TGF-beta-induced beta-catenin, which then undergoes proteasome-dependent degradation. TGF-beta-induced beta-catenin also regulates NR4A1 expression through formation of the beta-catenin-TCF-3/TCF-4/LEF-1 complex on the NR4A1 promoter. Thus, TGF-beta-induced nuclear export of NR4A1 in TNBC cells plays an essential role in cell migration, SMAD7 degradation, EMT, and induction of beta-catenin, and all of these pathways are inhibited by bis-indole-derived NR4A1 antagonists that inhibit nuclear export of the receptor and thereby block TGF-beta-induced migration and EMT.