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.

罗格列酮是过氧化物酶体增殖激活受体γ（PPARγ）的配体。然而，它通过PPARγ依赖性和独立机制发挥生物学活性和治疗作用。在这项研究中，我们定义罗格列酮也是类维生素A X受体α（RXRα）的配体，并显示出RXRα依赖性的活性。我们发现罗格列酮直接与RXRα的配体结合域（LBD）结合并诱导RXRα/ LBD四聚。罗格列酮可能通过抑制RXRα同源和异源二聚体来抑制激动剂诱导的RXRα同源二聚体和异源二聚体的转录活性。在急性早幼粒细胞白血病（APL）NB4细胞中，罗格列酮抑制RXRα/PML-RARα复合物形成并下调PML-RARα，从而抑制细胞增殖并诱导细胞分化。