Mechanisms of Tumor Promotion Effects of B[a]PDE

B[a]PDE的促癌作用机制

• 批准号: 7072773
• 负责人: CHUANSHU HUANG
• 金额: $ 35.27万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072773
• 关键词: AP1 protein; JUN kinase; benzopyrenediol epoxide; biological signal transduction; carbopolycyclic compound; chemical carcinogenesis; chemical related neoplasm /cancer; electron spin resonance spectroscopy; gel mobility shift assay; gene induction /repression; genetically modified animals; immunocytochemistry; laboratory mouse; luciferin monooxygenase; pathologic process; phosphatidylinositol 3 kinase; tissue /cell culture; tobacco

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are ubiquitous complete carcinogens that are present in tobacco smoke. The majority of work in previous studies has focused on the mutations that are associated with the tumor initiation effect of these compounds. However, the tumor promotion effect of PAHs, which is thought to be mediated through regulation of signal transduction pathways leading to activation of transcription factors, remains unclear. Our preliminary studies suggest that benzo[a]pyrene diol-epoxide (B[a]PDE), an ultimate carcinogenic metabolite of benzo[a]pyrene (B[a]P), is a major compound responsible for activation of the transcription factor activator protein-1 (AP-1) in non-cytotoxic concentrations. Since growing evidence has shown that activation of AP-1 by carcinogens is required for tumor promotion in both cell culture models and animal experiments, the main hypothesis of this proposal is that signal transduction pathways leading to activation of AP-1 play a critical role in the tumor promotion effect induced by B[a]PDE. The overall aim of this proposal is to elucidate the molecular mechanisms by which PAHs induce tumor promotion. Especially, we will establish the signal transduction pathways leading to AP-1 activation by B[a]PDE in a well-characterized tumor promotion cell culture model, mouse epidermal C141 cells. We will then investigate whether the same pathway occurs in an in vivo model using an AP-1-luciferase reporter transgenic mouse model. Furthermore, we will determine the role of AP-1 activation in B[a]PDE-induced tumor promotion in a two-stage carcinogenesis mouse skin model using dominant negative mutant c-jun (TAM67) transgenic mice. We will investigate these issues in accordance with the following testable hypotheses and specific aims: 1) To elucidate early events involved in initiating the signaling pathways leading to AP-1 activation by B[a]PDE in mouse epidermal C141 cells; 2) To test the hypothesis that the PI-3K/Akt/p7086k pathway is required for B[a]PDE-induced AP-1 activation in mouse epidermal C141 cells; 3) To determine whether B[a]PDE is able to induce AP-1 activation in vivo by using AP-1-luciferase reporter transgenic mice and whether this activation is through the same signal transduction pathways as in vitro; 4) To test the hypothesis that AP-1 activation is essential in the tumor promotion effect of B[a]PDE in a two-stage carcinogenesis mouse model. The significance of the research proposed in this application is that the results derived from the proposed studies will greatly facilitate the understanding of the molecular mechanism of cancer development caused by B[a]P and B[a]PDE. A better understanding of signal transduction pathways leading to AP-1 induction may provide valuable information needed for designing more effective agents for prevention and therapy of cancers caused by cigarette smoke. Such agents could interfere with the signaling pathways leading to AP-1 activation.

描述（由申请人提供）：多环芳烃（PAHS），例如苯并[A] pyrene（B [a] P），是烟草烟中存在的无处不在的完整癌。先前研究中的大多数工作都集中在与这些化合物的肿瘤起始作用相关的突变上。然而，尚不清楚PAH的肿瘤促进作用，被认为是通过调节信号转导途径介导的，导致转录因子激活。我们的初步研究表明，苯并[a] pyrene二醇（B [a] PDE）是苯并[A] pyrene（B [a] p）的最终致癌代谢物，是一种主要化合物，负责在非cy毒性中激活转录因子激活蛋白-1（AP-1）。由于越来越多的证据表明，在细胞培养模型和动物实验中，肿瘤促进需要通过致癌物激活AP-1，因此该提案的主要假设是，导致AP-1激活的信号转导途径在B [A] PDE引起的肿瘤促进效应中起关键作用。该提案的总体目的是阐明PAHS诱导肿瘤促进的分子机制。尤其是，我们将建立信号转导途径，从而导致B [A] PDE在特征良好的肿瘤促进细胞培养模型，小鼠表皮C141细胞中激活AP-1。然后，我们将使用AP-1-荧光素酶报告基因转基因小鼠模型在体内模型中研究相同的途径。此外，我们将使用显性负突变体C-JUN（TAM67）转基因小鼠在两阶段的癌变小鼠皮肤模型中确定AP-1激活在B [A] PDE诱导的肿瘤促进中的作用。我们将根据以下可检验的假设和特定目的研究这些问题：1）阐明引发小鼠表皮C141细胞B [A] PDE激活的信号传导途径所涉及的早期事件； 2）测试假设，即B [A] PDE诱导的小鼠表皮C141细胞中B [A] PDE诱导的AP-1激活需要PI-3K/AKT/P7086K途径； 3）确定B [a] PDE是否能够使用AP-1-荧光素酶报告基因转基因小鼠以及这种激活是否通过与体外相同的信号转导途径来诱导体内的AP-1激活； 4）测试假说，即AP-1激活在两阶段癌变小鼠模型中B [A] PDE的肿瘤促进作用至关重要。在本应用中提出的研究的重要性是，拟议的研究得出的结果将极大地促进对由B [A] P和B [A] PDE引起的癌症发展的分子机制的理解。对导致AP-1诱导的信号转导途径的更好理解可能会为设计更有效的药物预防和治疗由香烟烟雾引起的癌症所需的有价值的信息。这样的试剂可能会干扰导致AP-1激活的信号通路。