DELINEATING THE ROLE OF THE HOMOCYSTEINE-FOLATE-THYMIDYLATE SYNTHASE AXIS AND URACIL ACCUMULATION IN AFRICAN AMERICAN PROSTATE TUMORS

描述同型半胱氨酸-叶酸-胸苷酸合成酶轴和尿嘧啶积累在非裔美国人前列腺肿瘤中的作用

• 批准号: 10723833
• 负责人: Kimiko Krieger
• 金额: $ 10万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-21 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723833
• 关键词: 2' -Deoxythymidine; Affect; African American; Age; American; Anabolism; Automobile Driving; Base Excision Repairs; Biochemical; Biological; Biological Factors; Biological Markers; Biopsy; Cancer Patient; Carbon; Clinical; Collection; Communities; DNA Damage; DNA Repair; DNA Sequence Alteration; DNA lesion; Data; Data Set; Defect; Deoxyuridine; Detection; Diagnosis; Dietary Questionnaires; Disease; Disease Outcome; Disparity; Enzymes; European; Excision; Excision Repair; Exhibits; Folic Acid; Functional disorder; Genetic; Genomic Instability; Homocysteine; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Lesion; Link; Logistic Regressions; Logistics; Malignant Neoplasms; Malignant neoplasm of prostate; Malnutrition; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolism; Methionine; Methylenetetrahydrofolate reductase (NADPH); Modeling; Molecular; Neoplasm Metastasis; Outcome Measure; Pathway interactions; Patients; Plasma; Prostatectomy; Prostatic Neoplasms; Proteins; Pyrimidine; Recurrence; Regulation; Resistance; Risk; Role; Sampling; Scaffolding Protein; Socioeconomic Factors; Stress; Therapeutic; Therapeutic Intervention; Thymidylate Synthase; United States; Up-Regulation; Uracil; Vitamin B 12; Work; XRCC1 gene; advanced disease; base; biomarker development; cancer diagnosis; cancer health disparity; clinically relevant; cofactor; cohort; detection method; in vivo; inhibitor; inhibitor therapy; knock-down; men; novel; nucleotide metabolism; patient stratification; prostate cancer cell; prostate cancer progression; prostate cancer risk; repair function; repaired; response; small hairpin RNA; thymidylate; tumor; tumor growth

African American prostate cancer patients are known to be diagnosed at an earlier age, present with aggressive disease, and are twice as likely to succumb to prostate cancer than other demographic groups. Despite a major focus on socioeconomic factors, recent findings strongly argue for the existence of biological factors driving cancer disparities. In my efforts to understand biological drivers in prostate cancer, I applied a novel DNA damage detection method, Repair Assisted Damage Detection (RADD), and established that African American tumors have more DNA lesions overall than EA tumors, especially uracil lesions. Our lab has previously demonstrated that the homocysteine-methionine pathway is a metabolic hallmark of African American prostate cancers, which fuels the progression of the folate cycle that is required for the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). An upregulation of metabolites in the de novo pyrimidine biosynthesis pathway and altered levels of folate cycle metabolites were identified in African American prostate tumors, suggesting the link between uracil metabolism and uracil lesion accumulation. Uracil lesions are repaired by the base excision repair pathway. We have also shown that expression of XRCC1, a protein involved in coordinating base excision repair function, was lower in African American prostate tumors, indicative of defective base excision repair. These data collectively suggest that African American tumors exhibit the consequences of thymidylate stress, where the ability of thymidylate synthase (TYMS) to convert dUMP to dTMP is obstructed, resulting in dysregulation of base excision through the retention of uracil lesions. The increased amounts of uracil lesions in African American men could be a cumulative result of changes in nucleotide metabolism, which is caused by altered levels of components in the folate cycle and one-carbon metabolism. These components, such Vitamin B12 and folate, are known to be reduced in African American men, which could result from either dietary deficiencies or due to an aberrant homocysteine-methionine cycle, or both. While we understand the molecular consequences of reduced folate as it relates to uracil accumulation, the circumstances surrounding the DNA damage response through the regulation of Vitamin B12 and folate is currently unknown. The hypothesis of this proposal is that altered levels of Vitamin B12 and folate contribute to thymidylate stress, resulting in base excision repair pathway dysfunction and promoting prostate cancer progression in African American men. In this proposal, we will 1) determine the clinical relevance of homocysteine, Vitamin B12, and folate with prostate cancer progression in African American men and 2) elucidate the role of homocysteine, Vitamin B12, and folate regulation on TYMS function and base excision repair in African American prostate cancer patients. Successful completion of these aims will establish a link between metabolism and DNA repair in African American men with prostate cancer and help develop metabolic biomarkers to stratify these patients for DNA repair inhibitor therapies.

据了解，非裔美国前列腺癌​​患者诊断年龄较早，且病情呈侵袭性。 疾病，并且死于前列腺癌的可能性是其他人口群体的两倍。尽管有一个重大 关注社会经济因素，最近的研究结果强烈支持生物因素的存在 癌症差异。在我努力了解前列腺癌的生物驱动因素时，我应用了一种新型 DNA 损伤检测方法，修复辅助损伤检测（RADD），并建立了非裔美国人 肿瘤总体上比 EA 肿瘤有更多的 DNA 损伤，尤其是尿嘧啶损伤。我们实验室此前曾 证明同型半胱氨酸-蛋氨酸途径是非裔美国人前列腺的代谢标志 癌症，促进脱氧尿苷转化所需的叶酸循环的进展 单磷酸盐 (dUMP) 至脱氧胸苷单磷酸盐 (dTMP)。体内代谢物的上调 在非洲发现了新的嘧啶生物合成途径和叶酸循环代谢物水平的改变 美国前列腺肿瘤，提示尿嘧啶代谢与尿嘧啶病变积累之间的联系。尿嘧啶 病变通过碱基切除修复途径进行修复。我们还证明了 XRCC1 的表达， 参与协调碱基切除修复功能的蛋白质在非裔美国人前列腺肿瘤中较低， 表明碱基切除修复有缺陷。这些数据共同表明非洲裔美国人的肿瘤表现出 胸苷酸应激的后果，其中胸苷酸合酶 (TYMS) 将 dUMP 转化为 dTMP 受阻，通过尿嘧啶病变的保留导致碱基切除失调。这 非裔美国男性尿嘧啶病变数量的增加可能是以下变化的累积结果 核苷酸代谢，这是由叶酸循环和一碳成分水平改变引起的 代谢。众所周知，非洲裔美国人中这些成分（例如维生素 B12 和叶酸）的含量减少 男性，这可能是由于饮食不足或同型半胱氨酸-蛋氨酸循环异常造成的， 或两者兼而有之。虽然我们了解叶酸减少的分子后果，因为它与尿嘧啶积累有关， 通过维生素 B12 和叶酸的调节，围绕 DNA 损伤反应的环境是 目前未知。该提案的假设是维生素 B12 和叶酸水平的改变有助于 胸苷酸应激，导致碱基切除修复通路功能障碍，促进前列腺癌 非裔美国男性的进展。在本提案中，我们将 1) 确定临床相关性 同型半胱氨酸、维生素 B12 和叶酸与非裔美国男性前列腺癌进展的关系以及 2) 阐明同型半胱氨酸、维生素 B12 和叶酸调节对 TYMS 功能和碱基切除的作用 非裔美国前列腺癌​​患者的修复。成功完成这些目标将建立一个联系 患有前列腺癌的非洲裔美国男性的新陈代谢和 DNA 修复之间的关系，并帮助发展新陈代谢 生物标志物对这些患者进行 DNA 修复抑制剂治疗分层。