Abstract
TGFβ induces migration of lung cancer cells (A549, H460, and H1299), dependent on activation of c-Jun N-terminal kinase (JNK1), and is inhibited by the JNK1 inhibitor SP600125. Moreover, TGFβ-induced migration of the cells is also blocked by the nuclear export inhibitor leptomycin B (LMB) and the orphan nuclear receptor 4A1 (NR4A1) ligand 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (CDIM8), which retains NR4A1 in the nucleus. Subsequent analysis showed that the TGFβ/TGFβ receptor/PKA/MKK4 and -7/JNK pathway cascade phosphorylates and induces nuclear export of NR4A1, which in turn forms an active complex with Axin2, Arkadia (RNF111), and RNF12 (RLIM) to induce proteasome-dependent degradation of SMAD7 and enhance lung cancer cell migration. Thus, NR4A1 also plays an integral role in mediating TGFβ-induced lung cancer invasion, and the NR4A1 ligand CDIM8, which binds nuclear NR4A1, represents a novel therapeutic approach for TGFβ-induced blocking of lung cancer migration/invasion. IMPLICATIONS: Effective treatment of TGFβ-induced lung cancer progression could involve a number of agents including the CDIM/NR4A1 antagonists that block not only TGFβ-induced migration, but several other NR4A1-regulated prooncogenic genes/pathways in lung cancer cell lines.