Mitochondrial Reactive Oxygen and Tumor Promotion

描述：（申请人提供）癌症是发病的主要原因， 人口的死亡率。大量证据表明， 环境因素可能是人类癌症的主要原因。的 该项目的长期目标是研究 环境中的活性氧（ROS） 药物诱导的肿瘤促进。我们目前正在调查的假设是， 通过蛋白激酶C（PKC）介导的线粒体ROS诱导 信号转导是化学诱导肿瘤促进的机制。 因此，本提案的具体目标是：（1）调查 PKC诱导的细胞内ROS产生的机制 培养的表皮细胞，和（2）确定参与 PKC信号诱导的拟南芥源性活性氧在分子生物学中的作用 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JB 6细胞，一种流行的体外 肿瘤促进模型。广泛研究的PKC激活肿瘤 促进剂，12-0-十四酰基-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 技术将被应用于确定PKC同工酶（S）负责 诱导线粒体ROS，并检查PKC诱导的 在JB 6细胞的锚定非依赖性生长中， 细胞因子的激活被认为与 在肿瘤促进中。实现上述目标，将使 对大肠杆菌源性活性氧参与肿瘤促进的理解 不仅佛波醇酯的活性，而且其他PKC激活剂，如 石棉、香烟烟雾、雌激素、多氯联苯， 紫外线因为肿瘤的发展是 多阶段癌变，了解肿瘤发生机制 晋升将有助于我们预测风险的能力， 可能的化学保护和处理制度， 药物诱发的癌症

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.