Transforming Growth Factor /NR4A1-Inducible Breast Cancer Cell Migration and Epithelial-to-Mesenchymal Transition Is p38 (Mitogen-Activated Protein Kinase 14) Dependent.
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abstract
Transforming growth factor (TGF-)-induced migration of triple-negative 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- induces p38 (mitogen-activated protein kinase 14 [MAPK14]), which in turn phosphorylates NR4A1, resulting in nuclear export of the receptor. TGF-/p38 and NR4A1 also play essential roles in the induction of epithelial-to-mesenchymal transition (EMT) and induction of -catenin in TNBC cells, and these TGF--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. Inhibition of NR4A1 nuclear export results in nuclear export of TGF--induced -catenin, which then undergoes proteasome-dependent degradation. TGF--induced -catenin also regulates NR4A1 expression through formation of the -catenin-TCF-3/TCF-4/LEF-1 complex on the NR4A1 promoter. Thus, TGF--induced nuclear export of NR4A1 in TNBC cells plays an essential role in cell migration, SMAD7 degradation, EMT, and induction of -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--induced migration and EMT.
