Dietary Antioxidants, NF-KappaBeta, and Carcinogenesis

描述(由申请人提供) 饮食中的抗氧化剂已被证明可以抑制许多癌症的发生。 研究，但他们做到这一点的机制尚不清楚。一种可能性 它们影响氧化应激敏感型细胞的激活 转录因子，如核因子-kB。核因子-kB已被发现被激活 肝肿瘤促进剂，如多氯联苯、苯巴比妥和过氧化物酶 增殖物；已发现由过氧化物酶体增殖物激活的 至少部分地由活性氧调节。抗氧化剂维生素E 在体内和体内抑制由过氧化物酶体增殖物激活的核因子-kB 体外培养。维生素E抑制核因子-kB活化的能力是否 然而，其抗癌作用的原因尚不清楚。这个 P50亚基缺陷小鼠基因敲除模型的建立 核因子-kB将允许调查人员回答这个问题。他们发现了 过氧化物酶增殖物诱导细胞增殖的作用是 在这个模型中减少了。在这个项目中，调查人员提议测试 关于维生素E和其他抗氧化剂发挥抗衰老作用的假设 致癌作用至少部分是通过抑制核因子-kB的激活来实现的。这个 研究人员将使用p50基因敲除小鼠来检查维生素E诱导的 肝细胞增殖、凋亡、抗氧化状态和基因的变化 表达是由核因子-kB介导的。然后他们将确定是否会对 肿瘤的促进作用是由核因子-kB介导的。这些研究将表明，如果 抑制核因子-kB的激活对于抗癌作用是必要的 维生素E和其他抗氧化剂。这些结果将提供一种机械的 为可能的预防癌症的饮食建议提供依据。

DESCRIPTION (provided by applicant) Dietary antioxidants have been shown to inhibit carcinogenesis in many studies, but the mechanisms by which they do so are unclear. One possibility is that they influence the activation of oxidative stress-sensitive transcription factors, such as NF-kB. NF-kB has been found to be activated by hepatic tumor-promoting agents such as PCBs, phenobarbital, and peroxisome proliferators; the activation by peroxisome proliferators has been found to be mediated, at least in part, by active oxygen. The antioxidant vitamin E inhibits NF-kB activation by peroxisome proliferators, both in vivo and in vitro. Whether the ability of vitamin E to inhibit NF-kB activation is responsible for its anti-carcinogenic effect is unclear, however. The development of a knockout mouse model that is deficient in the p50 subunit of NF-kB will allow the investigators to answer this question. They have found that the cell proliferation-inducing effects of peroxisome proliferators are decreased in this model. In this project, the investigators propose to test the hypothesis that vitamin E and other antioxidants exert their anti- carcinogenic effects at least in part by inhibiting NF-kB activation. The investigators will use the p50 knockout mice to examine if vitamin E-induced changes in hepatic cell proliferation, apoptosis, antioxidant status, and gene expression are mediated by NF-kB. They will then determine if effects on tumor promotion are mediated by NF-kB. These studies will show if the inhibition of NF-kB activation is necessary for the anti-carcinogenic effects of vitamin E and other antioxidants. These results will provide a mechanistic basis for possible dietary recommendations to prevent cancer.