Zinc Chemoprevention of Arsenic Co-Carcinogenesis

锌对砷协同致癌作用的化学预防

• 批准号: 9325454
• 负责人: LAURIE G HUDSON
• 金额: $ 31.44万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325454
• 关键词: Address; Adverse effects; Affinity; Antioxidants; Arsenic; Arsenites; Base Excision Repairs; Benzo(a)pyrene; Binding; Biochemical; Biological Assay; Cadmium; Carcinogens; Cells; Chemoprevention; Chemoprotection; Chemoprotective Agent; Chromium; Coupled; Cysteine; DNA Binding; DNA Binding Domain; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Inhibition; DNA Repair Pathway; DNA Sequence Alteration; Elements; Employee Strikes; Epidemiology; Food; Foundations; Goals; Human; Intake; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Measures; Metals; Methods; Molecular Target; Mus; Mutagenesis; Nucleotide Excision Repair; Outcome; Outcome Study; Pathway interactions; Play; Poly(ADP-ribose) Polymerases; Population; Prevention strategy; Proteins; Publishing; Radiation Induced DNA Damage; Reporting; Research; Risk; Role; Skin; Skin Cancer; Skin Carcinogenesis; Skin Neoplasms; Smoking; Soil; Solid; Sun Exposure; Testing; UV induced; Ultraviolet Rays; Water; Work; Xeroderma Pigmentosum; Zinc; Zinc Fingers; Zinc supplementation; base; carcinogenesis; carcinogenicity; cost; enzyme activity; epidemiologic data; experimental study; exposed human population; functional restoration; genome integrity; genotoxicity; improved; in vivo; innovation; novel; oxidative DNA damage; prevent; public health relevance; repaired; synergism; synthetic peptide; tumorigenesis

DESCRIPTION (provided by applicant): There is strong evidence that in addition to the known direct carcinogenic actions of high arsenic concentrations, low, non-carcinogenic levels of arsenic synergize with other DNA-damaging agents such as benzo[a]pyrene and ultraviolet radiation (UVR) to enhance carcinogenesis. This observation has led to the identification of arsenic as a co-carcinogen. One mode of action to account for arsenic co-carcinogenesis is inhibition of DNA repair proteins containing zinc finger DNA binding motifs. Research from our lab demonstrates that: i) zinc finger proteins with e3 cysteine residues are direct molecular targets for arsenite binding, including xeroderma pigmentosum group A (XPA) and poly(ADP-ribose)polymerase (PARP)-1, which are the critical proteins for nucleotide excision repair (NER) and base excision repair (BER) respectively; ii) low levels of arsenite enhance UVR-induced photoproducts and oxidative DNA damage; and iii) supplemental zinc prevents arsenite effects on PARP-1 inhibition, enhancement of UVR-induced DNA damage and mutations. We hypothesize that zinc supplement will prevent arsenite enhancement of UVR-induced skin tumors by restoring the DNA repair capabilities in both BER and NER pathways. The proposed study will address a novel mechanism by which zinc may act to prevent arsenic-augmented carcinogenesis through interaction with distinct molecular targets in DNA repair pathways. In Aim 1, we will use multiple analytical approaches to definitively examine the competitive interaction of arsenite and zinc with synthetic peptides representing the PARP-1 and XPA zinc finger domains and with purified protein. These findings will be coupled with functional assays to establish the consequences of any identified differences in arsenite affinity for target proteins and zinc interactions. Aim 2 will analyze PARP-1 and XPA isolated from treated cells to measure arsenic and zinc binding to protein and the corresponding functional consequences to reveal the specific mechanism by which zinc reverses the arsenic effects. In Aim 3, we will validate PARP-1 and XPA as arsenic targets in vivo using biochemical methods, and test the hypothesis that zinc will prevent arsenic enhancement of UVR-induced DNA damage and skin tumors. The outcomes from the proposed studies are expected to demonstrate the capability of zinc to restore PARP-1 and XPA activity leading to improved genomic integrity and a decrease in the arsenic contribution to co-carcinogenesis. Although zinc has been considered chemoprotective largely through its reported general antioxidant activities, this proposal is innovative by focusing on a novel mechanism by which zinc prevents arsenite binding with specific zinc finger DNA repair protein targets, thus reversing the arsenite inhibition of DNA repair. This study will provide the solid foundations for a clear mechanistic understanding of how supplemental zinc reduces arsenic co-carcinogenesis, and provide the proof of principle for the potential of zinc supplement to prevent arsenic co-carcinogenesis. If validated, supplemental zinc could represent a low cost and easily implemented strategy for chemoprevention in arsenic exposed populations.

描述（由申请人提供）：有强有力的证据表明，除了高砷浓度的已知直接致癌作用外，砷与其他损伤剂（如苯甲酸酯[A] Pyrene和Ultraviolet辐射（UVR）相比，砷含量低，非癌水平，以增强脑力发生。这一观察结果导致砷作为共霉菌素的鉴定。考虑砷共癌发生的一种作用方式是抑制含有锌指DNA结合基序的DNA修复蛋白。我们实验室的研究表明：i）具有E3半胱氨酸残基的锌指蛋白是砷结合的直接分子靶标，包括Xeroderma chamosum a（XPA）（XPA）和poly（adp-ribose）聚合酶（PARP）-1，这是核底因修复（Nerer）的关键蛋白（nerer）的关键蛋白（nerer），这些蛋白（nerere）是cer（nerere）的临界（nerere）; ii）低水平的砷增强了UVR诱导的光产物和氧化DNA损伤； iii）补充锌防止砷对PARP-1抑制作用的影响，UVR诱导的DNA损伤的增强和突变。我们假设锌补充剂可以通过恢复BER和NER途径中的DNA修复能力来防止砷诱导的皮肤肿瘤的砷增强。拟议的研究将解决一种新的机制，锌可以通过与DNA修复途径中不同分子靶标的相互作用来作用以防止砷增强的癌变。在AIM 1中，我们将使用多种分析方法来确定检查砷和锌与代表PARP-1和XPA锌指域的合成肽的竞争相互作用以及具有纯化蛋白质的竞争相互作用。这些发现将与功能测定法相结合，以确定砷对靶蛋白和锌相互作用的砷亲和力差异的后果。 AIM 2将分析从处理的细胞中分离出的PARP-1和XPA，以测量砷和锌与蛋白质的结合以及相应的功能后果，以揭示锌逆转砷作用的特定机制。在AIM 3中，我们将使用生化方法验证PARP-1和XPA为体内砷靶标，并检验锌将防止UVR诱导的DNA损伤和皮肤肿瘤的砷增强的假设。拟议研究的结果有望证明锌恢复PARP-1和XPA活性的能力，从而改善基因组完整性，并降低砷对共癌发生的贡献。尽管锌在很大程度上被认为是通过报道的一般抗氧化剂活性而被认为是化学保护的，但该建议是通过关注一种新型机制来创新的，该机制通过该机制阻止了砷与特定的锌指DNA修复蛋白靶标结合，从而逆转了Arsenite抑制DNA修复的方法。这项研究将为固体基础提供清晰的机械理解，以了解补充锌如何减少砷的共癌发生，并为锌补充剂的潜在防止砷共霉菌生成提供原理证明。如果经过验证，补充锌可以代表低成本，并且容易实施砷暴露人群中化学预防的策略。