Alcohol and PAH-induced carcinogenesis

酒精和 PAH 诱发的致癌作用

• 批准号: 8502499
• 负责人: SUBODH KUMAR
• 金额: $ 7.2万
• 依托单位: BUFFALO STATE COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502499
• 关键词: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; AKT Signaling Pathway; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Apoptosis; Area; B-Lymphocytes; Benzo(a)pyrene; Benzopyrenes; Carcinogens; Cell Cycle; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cell Survival; Cells; Chemosensitization; Cigarette; Cytochromes; DNA; DNA Damage; DNA Synthesis Inhibition; DNA biosynthesis; Data; Epidemiologic Studies; Epithelial Cells; Epoxy Compounds; Ethanol; Ethanol Metabolism; Fibroblasts; G1/S Arrest; Genes; Genomics; Glycols; Health; Human; In Vitro; Induction of Apoptosis; Inhibition of Apoptosis; Investigation; JUN gene; Lung; Malignant neoplasm of esophagus; Measurement; Mediating; Metabolic Activation; Mitogens; Modeling; Mus; Organ; Pathway interactions; Phosphorylation; Physiological; Production; Protein p53; Radioactivity; Regulation; Relative Risks; Reporter; Research; Risk; Role; S Phase; Signal Pathway; Signal Transduction; Small Interfering RNA; Smoking; Testing; Therapeutic; Tobacco smoke; Transactivation; Transcription Factor AP-1; Tumor Promoters; Tumor Promotion; Tumor Suppressor Proteins; Up-Regulation; adduct; alcohol effect; alcohol exposure; benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; cancer prevention; carcinogenesis; carcinogenicity; cell growth; cell transformation; in vitro activity; response; tool

DESCRIPTION (provided by applicant): Epidemiological studies indicate that ethanol under certain conditions may function as co-carcinogen or tumor promoter. There is considerable evidence that alcohol abuse associated with smoking increases carcinogenic potential of tobacco smoke. The mechanism of potentiation of tobacco smoke-induced carcinogenicity by alcohol is not known. We observed that treatment of promotion sensitive JB6 Cl41 cells with (+/-)-anti- benzo[a]pyrene-7,8-diol-9,10-epoxide [anti-BPDE also called BPDE], an ultimate carcinogenic metabolite of benzopyrene (a carcinogenic PAH present in tobacco smoke) elicites DNA synthesis inhibition; and pre-treatment of cells with physiological concentration of ethanol relieves BPDE-induced DNA synthesis inhibition. Ethanol treatment does not have any effect on BPDE-DNA adduct formation which elicits cellular responses to BPDE. Previously we observed accumulation of p53 tumor suppressor protein and G1->S cell cycle arrest as well as cell transformation in response to BPDE treatment of JB6 cells. We hypothesize that one of the mechanisms of the potentiation of PAH-induced carcinogenicity by ethanol includes its ability to override DNA damage- induced cell cycle arrest via p53-dependent or p53-independent pathway and/or potentiation of cell survival through inhibition of apoptosis. Our studies in this proposal include examination of the effect of ethanol on BPDE-induced (1) anchorage- independent cell growth (in vitro measurement of potentiation of BPDE-induced cell transformation) and cell cycle profile, (2) p53 transactivating function (including stability/phosphorylation and activation) which leads to cell cycle arrest, as well as p53- independent (PI3-K/ ERK/c-Jun/AP-1 signaling) cell cycle arrest and (3) apoptosis response. Our studies will include in vitro study using promotion-sensitive mouse epidermal JB6 cells (widely used for tumor promotion studies) and human small airway epithelial (SAE) cells (relevant cell line for the study of tobacco smoke carcinogenesis). The overall objective of the proposal is to understand the underlying mechanism by which ethanol elicits its co-genotoxic effect with BPDE and thereby enhances PAH- induced carcinogenicity. Data obtained from these studies will help assessing the associated health risk presented by alcohol in presence of tobacco smoke constituents and will be useful to develop therapeutic strategies in the prevention of cancer.

描述（由申请人提供）：流行病学研究表明，乙醇在某些条件下可能充当共致癌物或肿瘤促进剂。有大量证据表明，与吸烟相关的酗酒会增加烟草烟雾的致癌潜力。酒精增强烟草烟雾诱发致癌性的机制尚不清楚。我们观察到，用(+/-)-抗苯并[a]芘-7,8-二醇-9,10-环氧化物[抗BPDE，也称为BPDE]（苯并芘（烟草烟雾中存在的一种致癌PAH）的最终致癌代谢物）处理促进敏感的JB6 Cl41细胞会引起DNA合成抑制；用生理浓度的乙醇预处理细胞可缓解BPDE诱导的DNA合成抑制。乙醇处理对 BPDE-DNA 加合物的形成没有任何影响，从而引起细胞对 BPDE 的反应。之前我们观察到 JB6 细胞 BPDE 处理后 p53 肿瘤抑制蛋白的积累和 G1->S 细胞周期停滞以及细胞转化。我们假设乙醇增强 PAH 诱导的致癌性的机制之一包括其通过 p53 依赖性或 p53 独立途径克服 DNA 损伤诱导的细胞周期停滞的能力和/或通过抑制细胞凋亡增强细胞存活。我们在本提案中的研究包括检查乙醇对 BPDE 诱导的 (1) 锚定非依赖性细胞生长（体外测量 BPDE 诱导的细胞转化的增强作用）和细胞周期特征，(2) 导致细胞周期停滞的 p53 反式激活功能（包括稳定性/磷酸化和激活），以及 p53 非依赖性细胞生长（PI3-K/ ERK/c-Jun/AP-1） 信号传导）细胞周期停滞和（3）细胞凋亡反应。我们的研究将包括使用促进敏感的小鼠表皮 JB6 细胞（广泛用于肿瘤促进研究）和人小气道上皮 (SAE) 细胞（用于研究烟草烟雾致癌作用的相关细胞系）进行体外研究。该提案的总体目标是了解乙醇与 BPDE 产生协同基因毒性作用的潜在机制，从而增强 PAH 诱导的致癌性。从这些研究中获得的数据将有助于评估烟草烟雾成分存在下酒精带来的相关健康风险，并将有助于制定预防癌症的治疗策略。