In vitro studies suggest that flavaglines target prohibitins as ligands, but this has not been established in the intestine ( 3). Our previous data suggest that F元 combats inflammation using a mouse model of colitis, although we did not elucidate the mechanism of F元 action ( 8). Previous studies demonstrated that F元 at nanomolar concentrations exhibits cytoprotective effects in neurons ( 6), cardiomyocytes ( 7), and intestinal epithelial cells ( 8) and presents little toxicity to healthy cells ( 3, 9, 10). F元 is a synthetic analogue of the flavagline rocaglaol, but lacking the structural components linked to causing MDR and suboptimal pharmacokinetics, making it an ideal candidate for further investigation ( 3, 5). Flavaglines have shown anticancer, anti-inflammatory, and cytoprotective activities in vitro ( 4). F元, therefore, represents a novel compound that combats Wnt pathway–dependent cancers, such as colorectal cancer.įlavaglines are a relatively new class of molecules derived from medicinal Aglaia (family Meliaceae) plants ( 3). These results suggest that F元 inhibits Wnt/β-catenin signaling via PHB1-dependent activation of Axin1. In colorectal cancer cells, F元 treatment blocked phosphorylation of PHB1 at Thr258, resulting in its nuclear translocation and binding to the Axin1 promoter. PHB1 deficiency in mice or in human colorectal cancer tumoroids abolished F元-induced expression of Axin1 and drove tumoroid death. F元 response was diminished in colorectal cancer cell lines and human colorectal cancer tumoroids harboring a mutation at S45 of β-catenin. F元 exhibited no change in cell viability in normal intestinal epithelial cells or human matched-normal colonoids. Here, we demonstrate that F元 combats intestinal tumorigenesis in the azoxymethane-dextran sodium sulfate and Apc Min/+ mouse models and in human colorectal cancer tumor organoids (tumoroids) by inhibiting Wnt/β-catenin signaling via induction of Axin1 expression. PHB1 is a highly conserved protein with diverse functions that depend on its posttranslational modifications and subcellular localization.
In vitro studies suggest that flavaglines target prohibitin 1 (PHB1) as a ligand, but this has not been established in the intestine. F元 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. 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. Colorectal cancer exhibits aberrant activation of Wnt/β-catenin signaling.
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