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Molecular Species Responsible for Tumor Suppressive Effect of MnSOD

负责 MnSOD 肿瘤抑制作用的分子种类

基本信息

批准号：
7261605
负责人：
LARRY OBERLEY
金额：
$ 24.86万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7261605
关键词：
Abbreviations Affect Amitrole Antioxidants Breast Buthionine Sulfoximine Carmustine Cell Line Cell Proliferation Cells Chemicals Complementary DNA Copper Data Deoxyglucose Ensure Enzymes Equilibrium Excision Genes Glioma Glucose Glucosephosphate Dehydrogenase Glutamate-Cysteine Ligase Glutathione Glutathione Disulfide Glutathione Reductase Growth Human Hydrogen Peroxide Infection Inhibition of Cancer Cell Growth Knowledge Location MCF7 cell MDA MB 231 Malignant - descriptor Manganese Manganese Superoxide Dismutase Measures Mitochondria Molecular Nitric Oxide Nitric Oxide Synthase Nitrogen Nitrosourea Compounds Non-Malignant Normal Cell Numbers Organelles Oxidation-Reduction Oxygen Pathway interactions Peroxidase Peroxidases Phosphogluconate Dehydrogenase Phospholipids Play Proteins Reactive Oxygen Species Reduced Glutathione Research Research Personnel Role Signal Transduction Pathway Small Interfering RNA Specificity Superoxide Dismutase Superoxides Transfection Triazoles Tumor Suppression Tumor Suppressor Proteins U118 Work Zinc anticancer treatment base cancer cell cancer therapy cancer type catalase cell type clinically relevant copper zinc superoxide dismutase dehydroepiandrosterone experience gamma-glutamylcysteine glucose oxidase glutathione peroxidase glutathione synthase inhibitor/antagonist malignant breast neoplasm malignant phenotype peroxiredoxin peroxisome phospholipid-hydroperoxide glutathione peroxidase programs protein expression research study tumor

项目摘要

DESCRIPTION (provided by applicant): The mitochondrial antioxidant enzyme manganese-containing superoxide dismutase (MnSOD) has been shown to be a tumor suppressor in a wide variety of different cancer cell types. In this application, we propose to examine the mechanism of tumor suppression by MnSOD. We will examine which reactive oxygen or nitrogen species is involved. We propose that there are only three logical possibilities: superoxide radical, hydrogen peroxide, or nitric oxide radical. We will transfect the cDNA for proteins that affect these molecules into MnSOD over-expressing human breast cancer and glioma cell lines and determine the effect on the malignant phenotype. The other proteins that will be over-expressed include two forms of glutathione peroxidase, catalase, and nitric oxide synthase. Moreover, the effect of inhibiting the activity of these proteins will be determined. Inhibition of glutathione peroxidase, catalase, and nitric oxide synthase will be accomplished by chemical inhibitors as well as antisense oligodeoxynucleotides and siRNAs. We will also transfect glucose oxidase into cancer cells and examine the effect on the malignant phenotype. Glucose oxidase produces hydrogen peroxide when glucose is present as substrate and thus this experiment will examine further if hydrogen peroxide is the effector molecule. If we can determine the molecular effector of the growth inhibitory effect of MnSOD over-expression, then we can use that knowledge to develop new anticancer treatments based on MnSOD over-expression and inhibition of the effector removal pathway. For example, we already have data showing hydrogen peroxide is involved in the growth suppressive effect of MnSOD over-expression and so we plan to study the antitumor effect of MnSOD over-expression combined with inhibitors of hydrogen peroxide removal. In this way, we hope to be able to develop exciting new cancer therapies.

描述（由申请人提供）：线粒体抗氧化酶含锰超氧化物歧化酶（MnSOD）已被证明是多种不同癌细胞类型中的肿瘤抑制因子。在本申请中，我们提出研究MnSOD抑制肿瘤的机制。我们将研究哪些活性氧或氮物种参与。我们提出只有三种逻辑可能性：超氧自由基、过氧化氢或一氧化氮自由基。我们将检测影响这些分子的蛋白质的cDNA进入MnSOD过表达的人乳腺癌和神经胶质瘤细胞系，并确定对恶性表型的影响。其他将被过度表达的蛋白质包括两种形式的谷胱甘肽过氧化物酶、过氧化氢酶和一氧化氮合酶。此外，将确定抑制这些蛋白质的活性的效果。谷胱甘肽过氧化物酶、过氧化氢酶和一氧化氮合酶的抑制将通过化学抑制剂以及反义寡脱氧核苷酸和siRNA来实现。我们还将葡萄糖氧化酶导入癌细胞，并检查其对恶性表型的影响。当葡萄糖作为底物存在时，葡萄糖氧化酶产生过氧化氢，因此本实验将进一步检查过氧化氢是否为效应分子。如果我们能够确定MnSOD过表达的生长抑制作用的分子效应物，那么我们可以利用这些知识开发基于MnSOD过表达和抑制效应物去除途径的新的抗癌治疗。例如，我们已经有数据显示过氧化氢参与MnSOD过表达的生长抑制作用，因此我们计划研究MnSOD过表达与过氧化氢去除抑制剂组合的抗肿瘤作用。通过这种方式，我们希望能够开发出令人兴奋的新癌症疗法。