CANCER PREVENTION & IMBALANCE IN PROTEIN PHOSPHORYLATION

癌症预防

• 批准号: 2103181
• 负责人: RAYUDU GOPALAKRISHNA
• 金额: $ 17.87万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-15 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2103181
• 关键词: antioxidants; carotene; chemical carcinogenesis; chemoprevention; dithiol; drug interactions; enzyme activity; gene induction /repression; hydrogen peroxide; laboratory mouse; laboratory rabbit; nutrition related tag; oncogenes; ornithine decarboxylase; peroxidation; phorbols; phosphoprotein phosphatase; phosphorylation; protein kinase C; selenium; sulfides; thiones; tissue /cell culture; tocopherols; tumor promoters

The long term goal of this study is to test a hypothesis that oxidants may induce an imbalance in protein phosphorylation systems, and chemopreventive antioxidants may counteract this process. Oxidants have emerged as important mediators of tumor promotion in one era of carcinogenesis research while protein kinase C (PKC) and protein phosphatase (PP) 1 and 2 A have emerged as receptors for tumor promoters in another. Nonetheless, the interlink between these mediators is poorly understood. Our preliminary studies revealed that oxidant tumor PP2A are susceptible to oxidative inactivation, oxidant tumor promoters may induce compartmentalization and imbalance in the PKC, PP1/PP2A system. Conversely, chemopreventive antioxidants may disrupt the cross- talk between the oxidants and the receptors for tumor promoters. These studies will be carried out with the C3H/10T1/2 cell line and an in vitro model of transformation. The primary focus is to understand the direct and indirect actions of oxidants that influence the PKC/PP system and its direct counteraction by antioxidants (indirect actions). Transformation- related studies will be restricted to induction of ornithine decarboxylase, c-fos, c-myc and in vitro scoring of the transformed foci. The first aim is to determine whether the oxidant tumor promoters H202, benzoyl peroxide and phorbol ester-induced oxidants can induce an imbalance or compartmentalization in PKC/PP. Then, studies are extended to understand how the imbalance in PKC/PP could affect the above mentioned transformation-related events. The second aim is to determine the abilities of nonsulfur chemopreventive agents, carotenoids (lycopene, Beta-carotene), vitamin E, and ellagic acid to counteract the oxidant effects on PKC, PP1, and PP2A. The third aim is to extend these studies to the organosulfur compounds diallysulfide and oltipraz (dithiolthiones) to assess whether the antioxidant actions of sulfur agents differ from that of nonsulfur agents. The final aim is to understand the interactions of chemopreventive agents that are effective in counteracting tumor promoters. The combination of selenium, vitamin E, Vitamin C, and diallylsulfide will be studied. The results of these studies may further help understand the molecular mechanisms involved in cancer chemoprevention.

这项研究的长期目标是检验一个假设，即氧化剂 可能会导致蛋白质磷酸化系统的失衡，以及 化学预防性抗氧化剂可能会抵消这一过程。氧化剂有 作为重要的促癌介质出现在一个时代 蛋白激酶C(PKC)与蛋白质的致癌研究 磷酸酶(PP)1和2 A已成为肿瘤促进剂的受体 在另一个地方。尽管如此，这些调解人之间的联系是 人们对此知之甚少。我们的初步研究表明，氧化剂肿瘤 PP2A易受氧化失活、氧化剂、肿瘤促进剂的影响 可能导致PKC、PP1/PP2A的区域化和失衡 系统。相反，化学预防性抗氧化剂可能会破坏这种交叉反应。 氧化剂和肿瘤促进剂受体之间的对话。这些 研究将在C3H/10T1/2细胞系和体外培养的 转型模式。主要的焦点是理解直接的 氧化剂对PKC/PP体系及体系的间接作用 抗氧化剂的直接反作用(间接作用)。转型- 相关研究将仅限于鸟氨酸的诱导 转化灶脱羧酶、c-fos、c-myc及体外评分。 第一个目标是确定氧化剂肿瘤促进剂H202， 过氧化苯甲酰和佛波酯诱导的氧化剂可以诱导 PKC/PP的不平衡或区隔。然后，扩展研究范围 了解PKC/PP失衡如何影响上述 提到了与转型相关的事件。第二个目标是确定 非硫化学防腐剂、类胡萝卜素(番茄红素、 β-胡萝卜素)、维生素E和鞣花酸来中和氧化剂 对PKC、PP1和PP2A的影响。第三个目标是扩展这些研究 对有机硫化合物二烯丙基硫化物和奥替普利(二硫代硫酮) 评估硫磺制剂的抗氧化作用是否不同于 非硫试剂的影响。最终的目标是理解 有效的化学预防药物之间的相互作用 对抗肿瘤促进剂。硒、维生素E、 维生素C和二烯丙基硫化物将被研究。这些研究的结果 研究可能有助于进一步了解参与的分子机制。 癌症化学预防。