Abstract：
In this study, we evaluated the effects of vitamin E δ-tocotrienol (DT3) and aspirin on Wnt signaling in human colon cancer stem cells (CCSCs) and in the prevention of adenoma formation in APCmin/+ mice. We found that knockdown of the adenomatous polyposis coli (APC) gene led to subsequent activation of Wnt signaling in colon epithelial cells (NCM460-APCsiRNA) and induction of β-catenin and its downstream target proteins c-MYC, cyclin D1, and survivin. When aspirin and DT3 were combined, cell growth and survival were inhibited and apoptosis was induced in colon epithelial cells and in CCSCs. However, DT3 and/or aspirin had little or no effect on control normal colon epithelial cells (NCM460-NCsiRNA). The induction of apoptosis was directly related to activation of caspase 8 and cleavage of BID to truncated BID. In addition, DT3 and/or aspirin-induced apoptosis was associated with cleaved PARP, elevated levels of cytosolic cytochrome c and BAX, and depletion of anti-apoptotic protein BCl-2 in CCSCs. The combination of aspirin and DT3 inhibited the self-renewal capacity, Wnt/β-catenin receptor activity, and expression of β-catenin and its downstream targets c-MYC, cyclin D1 and survivin in CCSCs. We also found that treatment with DT3 alone or combined with aspirin significantly inhibited intestinal adenoma formation and Wnt/ β-catenin signaling and induced apoptosis, compared to vehicle, in APCmin/+ mice. Our study demonstrated a rationale for further investigation of the combination of DT3 and aspirin for colorectal cancer prevention and therapy.
摘要：
在这项研究中,我们评估了维生素Eδ-生育三烯酚（DT3）和阿司匹林对人结肠癌干细胞（CCSCs）中Wnt信号传导的影响，以及在APCmin/+小鼠中预防腺瘤形成的影响。我们发现，结肠腺瘤性息肉病（APC）基因的敲除导致结肠上皮细胞（NCM460-APCsiRNA）中Wnt信号的随后激活和β-catenin及其下游靶蛋白c-MYC的诱导，cyclinD1和survivin。当阿司匹林和DT3联合使用时，结肠上皮细胞和CCSCs的细胞生长和存活被抑制，凋亡被诱导。然而,DT3和/或阿司匹林对对照正常结肠上皮细胞(NCM460-NCsiRNA)几乎没有或没有影响。凋亡的诱导与半胱天冬酶8的激活和BID裂解为截短的BID直接相关。此外,DT3和/或阿司匹林诱导的细胞凋亡与切割的PARP相关，细胞溶质细胞色素c和BAX水平升高，以及CCSCs中抗凋亡蛋白BCl-2的消耗。阿司匹林和DT3的组合抑制了自我更新能力，Wnt/β-catenin受体活性,β-catenin及其下游靶标c-MYC的表达，CCSCs中的cyclinD1和survivin。我们还发现，用DT3单独或与阿司匹林联合治疗显著抑制肠腺瘤的形成和Wnt/β-catenin信号传导，并诱导细胞凋亡。与车辆相比,在APCmin/+小鼠中。我们的研究证明了进一步研究DT3和阿司匹林联合用于预防和治疗结直肠癌的基本原理。
