School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, 361102, China.
School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, Fujian, 361102, China; High Throughput Drug Screening Platform, Xiamen University, Xiamen, Fujian, 361102, China.
Biochem Biophys Res Commun. 2020 Sep 10;530(1):160-166. doi: 10.1016/j.bbrc.2020.06.134. Epub 2020 Jul 30.
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物激活受体γ（PPARγ）的配体。然而，它通过 PPARγ 依赖和非依赖的机制发挥生物学活性和治疗作用。在本研究中，我们确定罗格列酮也是视黄酸 X 受体α（RXRα）的配体，并表现出 RXRα 依赖的活性。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 四聚体化。罗格列酮可能通过抑制 RXRα 同二聚体和异二聚体的形成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，罗格列酮通过抑制 RXRα/PML-RARα 复合物的形成和下调 PML-RARα，抑制细胞增殖并诱导细胞分化。总之，我们的研究确定了 RXRα 是罗格列酮的一个新靶点，RXRα 介导了罗格列酮的抗 APL 活性。
