Division of Gastroenterology, Department of Internal Medicine, Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, Texas.
Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, Colorado.
Cancer Res. 2020 Sep 1;80(17):3519-3529. doi: 10.1158/0008-5472.CAN-20-0216. Epub 2020 Jul 14.
Colorectal cancer exhibits aberrant activation of Wnt/β-catenin signaling. Many inhibitors of the Wnt/β-catenin pathway have been tested for Wnt-dependent cancers including colorectal cancer, but are unsuccessful due to severe adverse reactions. FL3 is a synthetic derivative of natural products called flavaglines, which exhibit anti-inflammatory and cytoprotective properties in intestinal epithelial cells, but has not been previously tested in cell or preclinical models of intestinal tumorigenesis. studies suggest that flavaglines target prohibitin 1 (PHB1) as a ligand, but this has not been established in the intestine. PHB1 is a highly conserved protein with diverse functions that depend on its posttranslational modifications and subcellular localization. Here, we demonstrate that FL3 combats intestinal tumorigenesis in the azoxymethane-dextran sodium sulfate and mouse models and in human colorectal cancer tumor organoids (tumoroids) by inhibiting Wnt/β-catenin signaling via induction of Axin1 expression. FL3 exhibited no change in cell viability in normal intestinal epithelial cells or human matched-normal colonoids. FL3 response was diminished in colorectal cancer cell lines and human colorectal cancer tumoroids harboring a mutation at S45 of β-catenin. PHB1 deficiency in mice or in human colorectal cancer tumoroids abolished FL3-induced expression of Axin1 and drove tumoroid death. In colorectal cancer cells, FL3 treatment blocked phosphorylation of PHB1 at Thr258, resulting in its nuclear translocation and binding to the Axin1 promoter. These results suggest that FL3 inhibits Wnt/β-catenin signaling via PHB1-dependent activation of Axin1. FL3, therefore, represents a novel compound that combats Wnt pathway-dependent cancers, such as colorectal cancer. SIGNIFICANCE: Targeting of PHB1 by FL3 provides a novel mechanism to combat Wnt-driven cancers, with limited intestinal toxicity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/17/3519/F1.large.jpg.
结直肠癌表现出 Wnt/β-连环蛋白信号的异常激活。许多 Wnt/β-连环蛋白途径的抑制剂已被用于包括结直肠癌在内的 Wnt 依赖性癌症的测试，但由于严重的不良反应而失败。FL3 是天然产物 flavaglines 的合成衍生物，在肠上皮细胞中具有抗炎和细胞保护特性，但尚未在肠道肿瘤发生的细胞或临床前模型中进行测试。研究表明 flavaglines 作为配体靶向抑制素 1 (PHB1)，但这在肠道中尚未得到证实。PHB1 是一种高度保守的蛋白质，具有多种功能，这些功能取决于其翻译后修饰和亚细胞定位。在这里，我们证明 FL3 通过诱导 Axin1 表达来抑制 Wnt/β-连环蛋白信号，从而在氧化偶氮甲烷-葡聚糖硫酸钠和小鼠模型以及人结直肠癌细胞类器官（类器官）中对抗肠道肿瘤发生。FL3 在正常肠上皮细胞或人匹配正常结肠类器官中对细胞活力没有影响。在结直肠癌细胞系和β-连环蛋白 S45 突变的人结直肠肿瘤类器官中，FL3 反应减弱。在小鼠或人结直肠肿瘤类器官中 PHB1 缺陷消除了 FL3 诱导的 Axin1 表达，并导致肿瘤类器官死亡。在结直肠癌细胞中，FL3 处理阻断 PHB1 在 Thr258 处的磷酸化，导致其核易位并与 Axin1 启动子结合。这些结果表明，FL3 通过 PHB1 依赖性激活 Axin1 抑制 Wnt/β-连环蛋白信号。因此，FL3 代表了一种通过靶向 PHB1 来抑制 Wnt 依赖性癌症（如结直肠癌）的新型化合物。意义：FL3 通过靶向 PHB1 提供了一种新的机制来对抗 Wnt 驱动的癌症，其肠道毒性有限。图形摘要：http://cancerres.aacrjournals.org/content/canres/80/17/3519/F1.large.jpg。
