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.

摘要 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)男性受前列腺癌的影响不成比例，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性测试 以及量身定做的治疗方法。导致前列腺癌健康的生物变化的原因有很多 差异已被提出，包括社会经济、遗传和环境因素。这些因素都是 引起新陈代谢改变，这是一种与前列腺癌的发生和发展相关的生物学变化。一项建议 这些变化如何驱动PCA的机制是通过产生反应性电泳体甲基乙醛 (毫克)。镁是脂肪、蛋白质和糖代谢的副产品，在DNA、RNA和 蛋白。这些被称为MG晚期糖基化终产物(MG-AGEs)的加合物会导致DNA突变和 基因组不稳定，改变RNA的稳定性和翻译，改变蛋白质的稳定性和功能。此外，MG- AGEs结合并激活AGEs受体(RAGE)。为了调节MG和MG-AGEs，细胞使用乙二醛酶1 (GLO1)解毒MG和可溶性RAGE(SRAGE)，以隔离MG-AGEs，防止RAGE激活。这些 组件被称为年龄/愤怒轴。我们的长期目标是定义MG-AGEs和 年龄/愤怒轴作为前列腺癌的生物标志物和驱动因素，并决定种族差异如何影响这一过程。 为了确定MG-AGEs、GLO1、RAGE和SRAGE与前列腺癌健康差异的关联，我们设计了一个 AA/B和EA患者有无PCA的嵌套式病例对照试验。我们用质量仪测定血清MG-AGE 用酶联免疫吸附试验测定血清sRAGE，并测定GLO1和AGE(编码RAGE的基因)的序列。 从全血中提取基因组DNA。我们发现MG-AGEs、SRAGE、GLO1和AGE SNPs 在AA/B男性中与前列腺癌显著相关，而在EA男性中则不显著。我们还观察到了一个显著的差异 这些成分在AA/B组和无PCA的EA组之间存在差异。这让我们假设MG-AGEs， SRAGE、GLO1和AGER SNPs可作为AA/B男性前列腺癌的生物标志物，GLO1 SNPs可作为PCa的生物标志物 可能在MG-AGEs的积聚、突变和PCa细胞生长中发挥作用。为了检验这一假设，我们 建议1)使用年龄/RAGE轴的分子和遗传特征以及人口统计学和临床 使用多变量临床-遗传风险模型预测AA/B和EA患者前列腺癌风险的变量和2) 用AA/B和EA-PCa肿瘤细胞系来确定GLO1单核苷酸对MG-AGE的影响 积累、细胞生长、转移标记物的表达和基因组突变的诱导。这 首次使用新型质谱仪对AA/B和EA患者的MG-AGEs进行了分析 方法，并描述了表达不同种族GLO1多态的细胞系的产生。