NRF2 level is negatively correlated with TGF-β1-induced lung cancer motility and migration via NOX4-ROS signaling.

Transforming growth factor-β1 (TGF-β1) is a multifaceted factor in cancer biology that regulates cell proliferation and migration. Overactivation of nuclear factor erythroid 2-like 2 (NFE2L2; NRF2) in cancers has been associated with facilitated tumor growth and therapy resistance; however, role in cancer migration has not been clearly explained yet. In this study, we investigated the role of NRF2 on TGF-β1-induced cell motility/migration. In NRF2-silenced lung cancer A549 cells, both basal and TGF-β1-inducible cell motility/migration increased compared to those in A549. SMAD transcription activity and phosphorylated SMAD2/3 levels were higher in TGF-β1-treated NRF2-low A549 cells than those in A549. Notably, the levels of reactive oxygen species (ROS) that were elevated by TGF-β1 treatment were higher in the NRF2-low A549 than those in control cells, and treatment with ROS scavenger blocked TGF-β1-induced cell motility. As an underlying molecular link, NADPH oxidase 4 (NOX4) was associated with higher ROS elevation and cell motility of NRF2-low A549. NOX4 and TGF-β1-inducible NOX4 levels were higher in NRF2-low A549 cells than those in A549. Moreover, the pharmacological inhibition of NOX4 blocked the TGF-β1-induced motility of NRF2-low A549 cells. Collectively, these results indicate that TGF-β1-induced cell motility/migration is facilitated in NRF2-inhibited lung cancer cells and that high levels of NOX4/ROS are associated with enhanced motility/migration.