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

SOD-1 在二十二碳六烯酸诱导的癌细胞细胞毒性中的作用

基本信息

批准号：
8359637
负责人：
Wei-Qun Ding
金额：
$ 10.97万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8359637
关键词：
Acids Antioxidants Attenuated Biological Biomedical Research DNA Binding Development Docosahexaenoic Acids Enzymes Funding Gene Expression Genes Genetic Transcription Grant Growth Human Indium Inhibition of Cancer Cell Growth Lipid Peroxidation Malignant Neoplasms Mammalian Cell Mediating Messenger RNA Molecular Molecular Target National Center for Research Resources Nude Mice Oklahoma Oxidative Stress Play Polyunsaturated Fatty Acids Prevention Principal Investigator Property Proteins Research Research Infrastructure Resources Role Signaling Molecule Source Stimulus Superoxides System Testing Time United States National Institutes of Health Xenograft Model anticancer activity base cancer cell cancer prevention cancer therapy cost cytotoxic cytotoxicity in vivo neoplastic cell novel novel strategies promoter superoxide dismutase 1 transcription factor

项目摘要

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.

该子项目是利用资源的众多研究子项目之一由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持并且子项目的首席研究员可能是由其他来源提供的，包括其他 NIH 来源。子项目可能列出的总成本代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。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作用的机制尚未完全阐明，但脂质过氧化的参与已得到充分认识。哺乳动物细胞中存在进化良好的抗氧化酶系统，在减轻各种细胞内和细胞外刺激引起的氧化应激方面发挥着重要作用。在主要抗氧化酶中，超氧化物歧化酶 1 (SOD-1) 具有减少细胞超氧化物的功能，并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降低癌细胞中 SOD-1 基因的表达，从而削弱细胞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 基因转录来降低 SOD-1 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。提出了两个具体目标来检验这一假设：1) 表征人类癌细胞中 DHA 诱导的 SOD-1 基因转录抑制的细胞机制。这项工作将主要致力于鉴定 SOD-1 基因启动子中介导 DHA 抑制作用的 DNA 结合元件以及所涉及的信号分子和转录因子。 2)考察SOD-1在DHA诱导的裸鼠异种移植模型中癌细胞生长抑制中的作用。这将重点确定改变的 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，并将有助于我们了解 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 将向 NIH 寻求独立的 RO1 资助，以继续这一研究方向。