Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 04310, Korea.
Department of Biochemistry and Molecular Biology, School of Medicine, Ajou University, Suwon, 16499, Korea.
Sci Rep. 2017 Apr 5;7:45951. doi: 10.1038/srep45951.
Colon cancer is one of the most common cancers. In this study, we isolated a lignan [(-)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol, DFS] from Alnus japonica (Betulaceae) and investigated its biological activity and mechanism of action on colon cancer. DFS reduced the viability of colon cancer cells and induced cell cycle arrest. DFS also suppressed β-catenin nuclear translocation and β-catenin target gene expression through a reduction in FoxM1 protein. To assess the mechanism of the action of DFS, we investigated the effect of DFS on endogenous and exogenous FoxM1 protein degradation in colon cancer cells. DFS-induced FoxM1 protein degradation was suppressed by lysosomal inhibitors, chloroquine and bafilomycin A1, but not by knock-down of proteasomal proteins. The mechanism of DFS for FoxM1 degradation is lysosomal dependent, which was not reported before. Furthermore, we found that FoxM1 degradation was partially lysosomal-dependent under normal conditions. These observations indicate that DFS from A. japonica suppresses colon cancer cell proliferation by reducing β-catenin nuclear translocation. DFS induces lysosomal-dependent FoxM1 protein degradation. This is the first report on the lysosomal degradation of FoxM1 by a small molecule. DFS may be useful in treating cancers that feature the elevated expression of FoxM1.
结直肠癌是最常见的癌症之一。在这项研究中，我们从桤木（桦木科）中分离出一种木脂素[（-）-（2R，3R）-1,4-O-二阿魏酰基去甲松柏醇，DFS]，并研究了其对结直肠癌细胞的生物学活性和作用机制。DFS 降低了结肠癌细胞的活力并诱导细胞周期停滞。DFS 还通过降低 FoxM1 蛋白来抑制β-连环蛋白核易位和β-连环蛋白靶基因的表达。为了评估 DFS 的作用机制，我们研究了 DFS 对结直肠癌细胞内源性和外源性 FoxM1 蛋白降解的影响。用溶酶体抑制剂氯喹和巴弗洛霉素 A1 抑制 DFS 诱导的 FoxM1 蛋白降解，但对蛋白酶体蛋白的敲低没有抑制作用。DFS 诱导的 FoxM1 蛋白降解依赖于溶酶体，这是以前没有报道过的。此外，我们发现 FoxM1 降解在正常条件下部分依赖于溶酶体。这些观察结果表明，来自桤木的 DFS 通过减少β-连环蛋白核易位来抑制结肠癌细胞的增殖。DFS 诱导溶酶体依赖性 FoxM1 蛋白降解。这是小分子诱导 FoxM1 溶酶体降解的首次报道。DFS 可能对治疗 FoxM1 表达升高的癌症有用。
