Identification of metabolic adducts associated with prostate cancer progression in African American men

鉴定与非裔美国男性前列腺癌进展相关的代谢加合物

• 批准号: 10721809
• 负责人: Sarah C. Shuck
• 金额: $ 46.65万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721809
• 关键词: Advanced Glycosylation End Products; African American; Age; American; Automobile Driving; Binding; Biological; Biological Assay; Biological Markers; Black race; Cancer Cell Growth; Cancer Etiology; Cell Line; Cell Proliferation; Cells; Cessation of life; Clinical; Clinical Data; Clustered Regularly Interspaced Short Palindromic Repeats; Control Groups; DNA; DNA Sequence Alteration; Data; Death Rate; Diagnostic tests; Disease; Disparity; Drug Metabolic Detoxication; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Equation; European; Frequencies; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genomic DNA; Genomic Instability; Genomics; Glutathione; Goals; Incidence; Individual; Induced Mutation; Inflammation; Knowledge; Lactoylglutathione Lyase; Lead; Lipids; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measures; Medical Genetics; Metabolic; Metabolism; Metastatic Prostate Cancer; Methods; Modeling; Molecular; Molecular Structure; Mutagenesis; Mutation; Neoplasm Metastasis; Outcome; PC3 cell line; Pathway interactions; Play; Process; Production; Prognosis; Proteins; Pyruvaldehyde; RNA; RNA Stability; Race; Reaction; Risk; Role; SNP array; Serum; Single Nucleotide Polymorphism; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Translations; Untranslated Regions; Whole Blood; Work; adduct; biomarker development; black men; cancer health disparity; case control; cell growth; cohort; control trial; design; differential expression; disparity reduction; high risk; men; mortality risk; novel; overexpression; polygenic risk score; predictive test; prevent; prostate cancer cell; prostate cancer model; prostate cancer progression; prostate cancer risk; racial difference; racial disparity; racial diversity; racial population; receptor for advanced glycation endproducts; risk prediction; socioeconomics; sugar; targeted treatment; tumor; tumor progression

Abstract Prostate cancer (PCa) is the second highest cause of cancer-related deaths in men. African American/Black (AA/B) men are disproportionally impacted by PCa with a 60% higher incidence of disease and a 2-3x fold increase in mortality risk compared to European American (EA) men. There is an urgent need to identify the underlying biological changes that give rise to this disparity to develop inclusive diagnostic and predictive tests and tailored therapeutic treatments. A myriad of causes for the biological changes that drive PCa health disparities have been proposed, including socioeconomic, genetic, and environmental factors. These factors all give rise to altered metabolism, a biological change associated with PCa onset and progression. A proposed mechanism for how these changes drive PCa is through the production of the reactive electrophile methylglyoxal (MG). MG is a by-product of lipid, protein, and sugar metabolism and forms covalent adducts on DNA, RNA, and protein. These adducts, termed MG-advanced glycation end products (MG-AGEs) lead to DNA mutations and genomic instability, change RNA stability and translation, and alter protein stability and function. In addition, MG- AGEs bind and activate the receptor for AGEs (RAGE). To regulate MG and MG-AGEs, cells use glyoxalase 1 (GLO1) to detoxify MG and soluble RAGE (sRAGE) to sequester MG-AGEs and prevent RAGE activation. These components are termed the AGE/RAGE axis. Our long-term goal is to define the role of MG-AGEs and the AGE/RAGE axis as biomarkers and drivers of PCa and determine how racial disparities influence this process. To define the association of MG-AGEs, GLO1, RAGE, and sRAGE with PCa health disparities, we designed a nested case-control trial of AA/B and EA men with and without PCa. We measured serum MG-AGEs using mass spectrometry, serum sRAGE using ELISA, and sequenced the GLO1 and AGER (gene encoding RAGE) loci in genomic DNA isolated from whole blood. We discovered that MG-AGEs, sRAGE, and GLO1 and AGER SNPs were significantly associated with PCa in AA/B men but not EA men. We also observed a significant difference between these components in AA/B and EA men without PCa. This led us to hypothesize that MG-AGEs, sRAGE, and GLO1 and AGER SNPs may have utility as biomarkers for PCa in AA/B men and that GLO1 SNPs may play a role in the accumulation of MG-AGEs, mutations, and PCa cell growth. To test this hypothesis, we propose to 1) use molecular and genetic features of the AGE/RAGE axis along with demographic and clinical variables to predict the risk of PCa in AA/B and EA men using a multivariable clinical-genetic risk model and 2) use cell lines derived from AA/B and EA PCa tumors to determine the impact of GLO1 SNPs on MG-AGE accumulation, cell growth, the expression of metastatic markers, and the induction of genomic mutations. This work represents the first analysis of MG-AGEs in AA/B and EA men with PCA, utilizes novel mass spectrometry methods, and describes generation of cell lines expressing GLO1 polymorphisms from diverse racial groups.

抽象的 前列腺癌（PCa）是男性癌症相关死亡的第二大原因。非裔美国人/黑人 (AA/B) 男性受 PCa 的影响尤为严重，其发病率高出 60%，是男性的 2-3 倍 与欧洲裔美国人 (EA) 男性相比，死亡风险增加。迫切需要确定 导致这种差异的潜在生物学变化，以开发包容性诊断和预测测试 和量身定制的治疗方法。促进 PCa 健康的生物变化有多种原因 已经提出了差异，包括社会经济、遗传和环境因素。这些因素都 引起代谢改变，这是一种与 PCa 发病和进展相关的生物变化。提议的 这些变化驱动 PCa 的机制是通过反应性亲电子试剂甲基乙二醛的产生 （MG）。 MG 是脂质、蛋白质和糖代谢的副产品，在 DNA、RNA 和 DNA 上形成共价加合物。 蛋白质。这些加合物被称为 MG 高级糖基化终末产物 (MG-AGE)，会导致 DNA 突变并 基因组不稳定，改变 RNA 稳定性和翻译，并改变蛋白质稳定性和功能。此外，MG- AGE 结合并激活 AGE 受体 (RAGE)。为了调节 MG 和 MG-AGE，细胞使用乙二醛酶 1 (GLO1) 解毒 MG，可溶性 RAGE (sRAGE) 隔离 MG-AGE 并防止 RAGE 激活。这些 组件被称为 AGE/RAGE 轴。我们的长期目标是定义 MG-AGE 的作用和 AGE/RAGE 轴作为 PCa 的生物标志物和驱动因素，并确定种族差异如何影响这一过程。 为了定义 MG-AGE、GLO1、RAGE 和 sRAGE 与 PCa 健康差异的关联，我们设计了一个 对患有和不患有 PCa 的 AA/B 和 EA 男性进行巢式病例对照试验。我们使用质量测量血清 MG-AGE 使用 ELISA 进行光谱分析、血清 sRAGE，并对 GLO1 和 AGER（编码 RAGE 的基因）位点进行测序 从全血中分离出基因组 DNA。我们发现 MG-AGE、sRAGE、GLO1 和 AGER SNP 与 AA/B 男性的 PCa 显着相关，但与 EA 男性无关。我们还观察到显着差异 AA/B 男性和无 PCa 的 EA 男性中的这些成分之间的差异。这使我们推测 MG-AGEs， sRAGE、GLO1 和 AGER SNP 可能可用作 AA/B 男性 PCa 的生物标志物，并且 GLO1 SNP 可能在 MG-AGE 积累、突变和 PCa 细胞生长中发挥作用。为了检验这个假设，我们 建议 1) 使用 AGE/RAGE 轴的分子和遗传特征以及人口统计和临床特征 使用多变量临床遗传风险模型预测 AA/B 和 EA 男性 PCa 风险的变量和 2) 使用源自 AA/B 和 EA PCa 肿瘤的细胞系来确定 GLO1 SNP 对 MG-AGE 的影响 积累、细胞生长、转移标记物的表达以及基因组突变的诱导。这 这项工作首次对患有 PCA 的 AA/B 和 EA 男性中的 MG-AGE 进行了分析，采用了新型质谱法 方法，并描述了来自不同种族群体的表达 GLO1 多态性的细胞系的产生。