Berberine binds RXRα to suppress β-catenin signaling in colon cancer cells.
Berberine binds RXRα to suppress β-catenin signaling in colon cancer cells.
复制标题
小檗碱结合 RXR α 抑制结肠癌细胞中的 β-连环蛋白信号传导
作者：
Ruan H;Zhan YY;Hou J;Xu B;Chen B;Tian Y;Wu D;Zhao Y;Zhang Y;Chen X;Mi P;Zhang L;Zhang S;Wang X;Cao H;Zhang W;Wang H;Li H;Su Y;Zhang XK;Hu T
小檗碱是一种异喹啉类生物碱，是传统的东方药物，用于治疗腹泻和胃肠炎。最近，我们报道它可以通过下调β-catenin信号抑制动物和家族性腺瘤性息肉病患者肠息肉的生长。然而，介导黄连素作用的细胞内靶点仍然难以捉摸。在这里，我们提供了黄连素通过直接结合到核受体维甲酸X受体α（RXRα）中包含残基Gln 275，Arg 316和Arg 371的独特区域来抑制β-catenin功能的证据，其中黄连素伴随结合并协同激活RXRα与9-cis-retinoic acid（9-cis-RA），9-cis-RA是与RXRα的经典配体结合口袋结合的天然配体。小檗碱结合促进RXRα与核β-catenin的相互作用，导致c-Cbl介导的β-catenin降解，从而抑制结肠癌细胞的增殖。小檗碱对人结肠癌裸鼠移植瘤的生长有抑制作用，且抑制作用与RXRα的表达有关。总之，我们的研究不仅确定了RXRα是小檗碱的直接蛋白靶点，而且还剖析了它们的结合模式，并验证了小檗碱确实通过结合RXRα抑制结肠癌中的β-catenin信号传导和细胞生长，这为设计新的基于RXRα的抗肿瘤药物和药物组合提供了新的策略。
Berberine, an isoquinoline alkaloid, is a traditional oriental medicine used to treat diarrhea and gastroenteritis. Recently, we reported that it could inhibit the growth of intestinal polyp in animals and in patients with the familial adenomatous polyposis by downregulating β-catenin signaling. However, the intracellular target mediating the effects of berberine remains elusive. Here, we provide evidence that berberine inhibits β-catenin function via directly binding to a unique region comprising residues Gln275, Arg316 and Arg371 in nuclear receptor retinoid X receptor alpha (RXRα), where berberine concomitantly binding to and synergistically activating RXRα with 9-cis-retinoic acid (9-cis-RA), a natural ligand binding to the classical ligand-binding pocket of RXRα. Berberine binding promotes RXRα interaction with nuclear β-catenin, leading to c-Cbl mediated degradation of β-catenin, and consequently inhibits the proliferation of colon cancer cells. Furthermore, berberine suppresses the growth of human colon carcinoma xenograft in nude mice in an RXRα-dependent manner. Together, our study not only identifies RXRα as a direct protein target for berberine but also dissects their binding mode and validates that berberine indeed suppresses β-catenin signaling and cell growth in colon cancer via binding RXRα, which provide new strategies for the design of new RXRα-based antitumor agents and drug combinations.
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影响因子：
10.5
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