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Mitochondrial Reactive Oxygen and Tumor Promotion

线粒体活性氧与肿瘤促进

基本信息

批准号：
6354375
负责人：
YUNBO LI
金额：
$ 16万
依托单位：
ST. JOHN'S UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-10 至 2004-06-30
项目状态：
已结题

项目摘要

DESCRIPTION: (PROVIDED BY APPLICANT) Cancer is a leading cause of morbidity and mortality of the human population. Considerable evidence suggests that environmental agents may be the principal causes of human cancers. The long-term objective of this project is to investigate the role of mitochondria-derived reactive oxygen species (ROS) in environmental agent-induced tumor promotion. The hypothesis we are currently investigating is that induction of ROS from mitochondria through protein kinase C (PKC)-mediated signal transduction is a mechanism of chemically induced tumor promotion. Accordingly, the specific aims of this proposal are designed to (1) investigate the mechanisms underlying PKC-induced production of mitochondria-derived ROS in cultured epidermal cells, and (2) determine the involvement of mitochondria-derived ROS induced by PKC signaling in molecular and biochemical alterations leading to tumor promotion in vitro. To achieve these goals, mouse keratinocyte cell line MEL-30 and the epidermal JB6 cells, a popular in vitro tumor promotion model, will be used. The widely studied PKC-activating tumor promoter, 12-0-tetradecanoyl-phorbol-13-acetate (TPA) will be utilized as a model chemical to investigate the above hypothesis. Biochemical and molecular techniques will be applied to determine the PKC isozyme(s) responsible for the induction of mitochondrial ROS and to examine the role of PKC-induced mitochondria-derived ROS in anchorage-independent growth of JB6 cells as well as activation of cellular factors that are believed to be critically involved in tumor promotion. Fulfillment of the above aims will result in a greater understanding of the involvement of mitochondria-derived ROS in tumor promoting activities of not only phorbol esters, but other PKC-activating agents, such as asbestos, cigarette smoke, estrogens, polychlorinated biphenyls, and ultraviolet light. Because tumor promotion is the rate-limiting step in multistage carcinogenesis, knowledge of the mechanisms underlying tumor promotion will contribute to our ability to predict risk and to develop possible chemoprotective and treatment regimes against environmental agent-induced cancers.

描述：（由申请人提供）癌症是人类发病和死亡的主要原因。大量证据表明环境因素可能是人类癌症的主要原因。这该项目的长期目标是调查环境中线粒体衍生的活性氧（ROS）药物诱导的肿瘤促进。我们目前正在研究的假设是通过蛋白激酶 C (PKC) 介导从线粒体诱导 ROS 信号转导是化学诱导肿瘤促进的一种机制。因此，本提案的具体目标旨在 (1) 调查 PKC 诱导线粒体衍生 ROS 产生的机制培养的表皮细胞，以及（2）确定参与分子和生化中 PKC 信号传导诱导的线粒体衍生的 ROS 导致体外肿瘤促进的改变。为了实现这些目标，鼠标角质形成细胞系 MEL-30 和表皮 JB6 细胞（一种流行的体外实验）肿瘤促进模型，将被使用。广泛研究的 PKC 激活肿瘤启动子，12-0-十四烷酰基-佛波醇-13-乙酸酯（TPA）将被用作模型化学来研究上述假设。生化和分子将应用技术来确定负责的 PKC 同工酶诱导线粒体 ROS 并检查 PKC 诱导的作用线粒体衍生的 ROS 也参与 JB6 细胞贴壁依赖性生长作为被认为至关重要的细胞因子的激活在肿瘤促进方面。上述目标的实现将带来更大的了解线粒体衍生的 ROS 在肿瘤促进中的作用不仅是佛波酯的活性，还有其他 PKC 激活剂的活性，例如石棉、香烟烟雾、雌激素、多氯联苯和紫外线。因为肿瘤促进是限速步骤多阶段癌变，了解肿瘤的机制晋升将有助于我们预测风险和发展的能力可能的针对环境的化学保护和治疗方案药物诱发的癌症。