THE ROLE OF SOD-1 IN DOCOSAHAXAENOIC ACID-INDUCED CYTOTOXICITY IN CANCER CELLS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 二十二碳六烯酸(DHA 22：6)是一种已知具有抗癌特性的长链n-3多不饱和脂肪酸。虽然DHA对肿瘤细胞的生长抑制和细胞毒作用的机制尚未完全阐明，但人们已经很好地认识到DHA参与了脂质过氧化。哺乳动物细胞中存在着进化良好的抗氧化酶系统，它们在减轻各种细胞内外刺激引起的氧化应激中发挥着重要作用。在主要的抗氧化酶中，超氧化物歧化酶-1(SOD-1)具有还原细胞超氧化物歧化的功能，被认为是癌症治疗的潜在分子靶点。我们最近证明，DHA选择性地在mRNA和蛋白质水平上降低癌细胞中SOD-1基因的表达，从而削弱细胞的抗氧化力，增强氧化潜能。我们的初步研究进一步表明，DHA通过抑制SOD-1基因转录而降低了SOD-1的mRNA水平。因此，我们假设靶向SOD-1是DHA发挥抗癌作用的一种新的细胞机制。提出了两个特定的目的来验证这一假说：1)表征DHA抑制人癌细胞中SOD-1基因转录的细胞机制。这项工作将主要是为了确定在SOD-1基因启动子中介导DHA抑制效应的DNA结合元件以及相关的信号分子和转录因子。2)探讨SOD-1在DHA抑制裸鼠移植瘤生长中的作用。这将集中于确定改变的SOD-1基因表达对DHA诱导的体内癌细胞生长抑制的影响。拟议的研究与人类癌症的预防和治疗直接相关，并将有助于我们理解DHA抗癌活性的细胞和分子机制。预计拟议研究的结果将为开发使用DHA预防和/或治疗癌症的新策略提供生物学基础。届时，PI将从NIH寻求独立的RO1资金，以继续这一系列研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Docosahexaenoic acid (DHA 22:6) is a long chain n-3 polyunsaturated fatty acid that is known to have anticancer properties. While the mechanisms of the growth inhibitory and cytotoxic effects of DHA on tumor cells are yet to be fully elucidated, the involvement of lipid peroxidation has been well recognized. There are well-evolved antioxidant enzyme systems in mammalian cells, which play an important role in attenuating oxidative stress caused by various intra- and extra- cellular stimuli. Among the primary antioxidant enzymes, superoxide dismutase 1 (SOD-1) functions in reducing cellular superoxides and has been suggested to be a potential molecular target for cancer therapy. We have recently demonstrated that DHA selectively reduces SOD-1 gene expression in cancer cells at mRNA and protein levels, thereby weakening cellular antioxidant forces and enhancing oxidative potential. Our preliminary studies further show that DHA lowers mRNA levels of SOD-1 by suppressing SOD-1 gene transcription. We therefore hypothesize that targeting SOD-1 is a novel cellular mechanism whereby DHA exerts its anticancer action. Two specific aims are proposed to test this hypothesis:1) To characterize the cellular mechanisms of DHA-induced suppression of SOD-1 gene transcription in human cancer cells. This effort will be primarily directed to identify DNA binding elements in the SOD-1 gene promoter that mediate DHA's suppressive effect and the signaling molecules and transcription factors involved. 2) To examine the role of SOD-1 in DHA-induced growth inhibition of cancer cells in nude mouse xenograft models. This will focus on determining the effects of altered SOD-1 gene expression on DHA-induced growth inhibition of cancer cells in vivo. The proposed studies are directly relevant to the prevention and treatment of human cancer and will contribute to our understanding of the cellular and molecular mechanisms underlying DHA's anticancer activity. It is anticipated that results derived from the proposed studies will provide a biological basis for the development of novel strategies for cancer prevention and/or treatment using DHA. At that time the PI will seek independent RO1 funding from NIH to continue this line of research.