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

• 批准号: 8167547
• 负责人: Wei-Qun Ding
• 金额: $ 10.78万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167547
• 关键词: Acids; Antioxidants; Attenuated; Biological; Computer Retrieval of Information on Scientific Projects Database; DNA Binding; Development; Docosahexaenoic Acids; Enzymes; Funding; Gene Expression; Genes; Genetic Transcription; Grant; Growth; Human; Indium; Inhibition of Cancer Cell Growth; Institution; Lipid Peroxidation; Malignant Neoplasms; Mammalian Cell; Mediating; Messenger RNA; Molecular; Molecular Target; Nude Mice; Oxidative Stress; Play; Polyunsaturated Fatty Acids; Prevention; Property; Proteins; Research; Research Personnel; 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; cytotoxic; cytotoxicity; in vivo; neoplastic cell; novel; novel strategies; promoter; superoxide dismutase 1; transcription factor

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 Docosahexaenoic Acid（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。 尽管尚未完全阐明DHA对DHA对肿瘤细胞的生长抑制和细胞毒性作用的机制，但脂质过氧化的参与已得到充分认识。 哺乳动物细胞中有良好发展的抗氧化酶系统，在衰减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。 在原发性抗氧化剂酶中，超氧化物歧化酶1（SOD-1）在还原细胞超氧化物中起作用，并被认为是癌症治疗的潜在分子靶标。 我们最近证明，DHA在mRNA和蛋白质水平上有选择地降低癌细胞中的SOD-1基因表达，从而削弱了细胞抗氧化作用并增强氧化潜力。 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的mRNA水平。 因此，我们假设靶向SOD-1是一种新型的细胞机制，DHA发挥了其抗癌作用。 提出了两个具体目的来检验这一假设：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。这项工作将主要针对SOD-1基因启动子中介导DHA的抑制作用以及所涉及的信号分子和转录因子中的DNA结合元件。 2）检查SOD-1在DHA诱导的裸鼠异种移植模型中癌细胞的生长抑制作用中的作用。这将着重确定改变SOD-1基因表达对DHA诱导的体内癌细胞生长抑制的影响。 拟议的研究与预防和治疗人类癌症直接相关，将有助于我们对DHA抗癌活性下的细胞和分子机制的理解。 预计从拟议的研究中得出的结果将为使用DHA的癌症预防和/或治疗的新策略提供生物学基础。当时，PI将寻求NIH的独立RO1资金，以继续这一研究。