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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 二十二碳六烯酸（DHA 22：6）是一种长链n-3多不饱和脂肪酸，已知具有抗癌特性。 虽然DHA对肿瘤细胞的生长抑制和细胞毒性作用的机制尚未完全阐明，但脂质过氧化的参与已被充分认识。 在哺乳动物细胞中存在进化完善的抗氧化酶系统，其在减轻由各种细胞内和细胞外刺激引起的氧化应激中起重要作用。 在主要的抗氧化酶中，超氧化物歧化酶1（SOD-1）的功能是减少细胞内的超氧化物，并已被认为是癌症治疗的潜在分子靶点。 我们最近证明，DHA在mRNA和蛋白质水平上选择性地降低癌细胞中SOD-1基因的表达，从而削弱细胞的抗氧化力并增强氧化潜力。 我们的初步研究进一步表明，DHA通过抑制SOD-1基因转录降低SOD-1的mRNA水平。 因此，我们假设，针对SOD-1是一种新的细胞机制，DHA发挥其抗癌作用。 本研究的主要目的是：（1）探讨DHA抑制肿瘤细胞SOD-1基因转录的细胞机制。这项工作将主要致力于确定SOD-1基因启动子中介导DHA抑制作用的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诱导的裸鼠移植瘤细胞生长抑制中的作用。这将集中于确定改变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，并将有助于我们了解DHA抗癌活性的细胞和分子机制。 预计来自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RO 1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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.