Rosiglitazone binds to RXRα to induce RXRα tetramerization and NB4 cell differentiation

Biochem Biophys Res Commun. 2020 Sep 10;530(1):160-166. doi: 10.1016/j.bbrc.2020.06.134. Epub 2020 Jul 30.

Abstract

Rosiglitazone is a ligand of peroxisome proliferation-activated receptor gamma (PPARγ). However, it exerts biological activities and therapeutic effects through both PPARγ-dependent and independent mechanisms. In this study, we defined that rosiglitazone was also a ligand of retinoid X receptor alpha (RXRα) and displayed RXRα-dependent activities. We found that rosiglitazone directly bound to the ligand binding domain (LBD) of RXRα and induced RXRα/LBD tetramerization. Rosiglitazone inhibited the agonist-induced transcriptional activity of RXRα homodimers and heterodimers likely through inhibiting RXRα homo- and hetero-dimerization. In acute promyelocytic leukemia (APL) NB4 cells, rosiglitazone inhibited cell proliferation and induced cell differentiation, resulting from inhibiting RXRα/PML-RARα complex formation and down-regulating PML-RARα. Together, our study identified RXRα as a novel target of rosiglitazone and RXRα mediating the anti-APL activity of rosiglitazone.

Keywords: Acute promyelocytic leukemia; PML-RARα; Peroxisome proliferation-activated receptor gamma; Retinoid X receptor alpha; Rosiglitazone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Leukemia, Promyelocytic, Acute / metabolism
  • Protein Multimerization / drug effects*
  • Retinoid X Receptor alpha / metabolism*
  • Rosiglitazone / pharmacology*

Substances

  • Hypoglycemic Agents
  • RXRA protein, human
  • Retinoid X Receptor alpha
  • Rosiglitazone