Rexinoid inhibits Nrf2-mediated transcription through retinoid X receptor alpha.

Abstract NF-E2 P45-related factor 2 (Nrf2) is a key transcription factor that controls genes encoding cytoprotective and detoxifying enzymes through antioxidant response elements (AREs) in their regulatory regions. We reported recently that retinoid X receptor alpha (RXRα) inhibits Nrf2 function by direct interaction with the Neh7 domain of Nrf2 in a ligand-independent manner. Here, we provide evidence that an RXRα-specific ligand, bexarotene, dose-dependently inhibits the mRNA expression of ARE-driven genes. Knock-down of RXRα by siRNA abolished the inhibitory effect of bexarotene. Conversely, the over-expression of RXRα enhanced the inhibition by bexarotene, indicating that the effect is mediated by RXRα. The inhibition by bexarotene was also found in the non-small-cell lung cancer cell line A549, which carries a dysfunctional somatic mutation of Kelch-like ECH-associated protein 1 (KEAP1), suggesting that KEAP1 is not involved. Our results demonstrate that rexinoid is able to inhibit the transcriptional activity of Nrf2, and that RXRα can repress the cytoprotection pathway in a ligand-dependent manner.