Rexinoid inhibits Nrf2-mediated transcription through retinoid X receptor alpha

Biochem Biophys Res Commun. 2014 Sep 26;452(3):554-9. doi: 10.1016/j.bbrc.2014.08.111. Epub 2014 Aug 27.

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.

Keywords: Bexarotene; Nrf2; RXRα.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Antioxidant Response Elements
  • Bexarotene
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kelch-Like ECH-Associated Protein 1
  • Mutation
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Retinoid X Receptor alpha / antagonists & inhibitors
  • Retinoid X Receptor alpha / genetics*
  • Retinoid X Receptor alpha / metabolism
  • Signal Transduction
  • Tetrahydronaphthalenes / pharmacology*
  • Transcription, Genetic

Substances

  • Anticarcinogenic Agents
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • Retinoid X Receptor alpha
  • Tetrahydronaphthalenes
  • Bexarotene