TGFβ-induced Lung Cancer Cell Migration is NR4A1-dependent

Abstract

Transforming growth factor β (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 which block not only TGFβ-induced migration but several other NR4A1-regulated pro-oncogenic genes/pathways in lung cancer cell lines.