Effect of vitamin E δ-tocotrienol and aspirin on Wnt signaling in human colon cancer stem cells and in adenoma development in APCmin/+ mice.

IF 3.3 3区 医学 Q2 ONCOLOGY
Kazim Husain, Domenico Coppola, Chung S Yang, Mokenge P Malafa
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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.

维生素 E δ-生育三烯酚和阿司匹林对人类结肠癌干细胞 Wnt 信号转导和 APCmin/+ 小鼠腺瘤发育的影响
在这项研究中,我们评估了维生素 E δ-生育三烯酚(DT3)和阿司匹林对人类结肠癌干细胞(CCSCs)中 Wnt 信号转导的影响,以及对预防 APCmin/+ 小鼠腺瘤形成的影响。我们发现,敲除腺瘤性息肉病大肠杆菌(APC)基因会导致结肠上皮细胞(NCM460-APCsiRNA)的 Wnt 信号随之激活,并诱导 β-catenin及其下游靶蛋白 c-MYC、细胞周期蛋白 D1 和存活素。当阿司匹林和 DT3 合用时,结肠上皮细胞和 CCSCs 的细胞生长和存活受到抑制,细胞凋亡被诱导。然而,DT3 和/或阿司匹林对对照组正常结肠上皮细胞(NCM460-NCsiRNA)几乎没有影响。细胞凋亡的诱导与 caspase 8 的激活和 BID 被裂解为截短的 BID 直接相关。此外,DT3和/或阿司匹林诱导的细胞凋亡与PARP裂解、细胞色素c和BAX水平升高以及CCSCs中抗凋亡蛋白BCl-2的耗竭有关。阿司匹林和DT3联合使用可抑制CCSCs的自我更新能力、Wnt/β-catenin受体活性、β-catenin及其下游靶标c-MYC、cyclin D1和survivin的表达。我们还发现,与药物治疗相比,DT3 单独或与阿司匹林联合治疗可显著抑制 APCmin/+ 小鼠肠腺瘤的形成和 Wnt/β-catenin 信号转导,并诱导细胞凋亡。我们的研究为进一步研究 DT3 和阿司匹林联合用于预防和治疗结直肠癌提供了理论依据。
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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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