Bacteria-derived xenobiotics in colon cancer prevention: Link to GPR109A and colonic ketogenesis

细菌源性异生素在结肠癌预防中的作用：与 GPR109A 和结肠生酮的联系

• 批准号: 10737017
• 负责人: Muthusamy Thangaraju
• 金额: $ 42.96万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737017
• 关键词: Affect; Affinity; Agonist; American; Anti-Inflammatory Agents; Azoxymethane; Bacteria; Benzo(a)pyrene; Binding; Biological; Biological Process; Butyrates; Carcinogens; Cell Surface Receptors; Cells; Cessation of life; Chemical Models; Colon; Colon Carcinoma; Colonic inflammation; Coupled; Deacetylase; Deacetylation; Dendritic Cells; Diagnosis; Diet; Disease; Dose; Dyslipidemias; Enzymes; Epithelium; Evaluation; Exposure to; FDA approved; Fermentation; Frequencies; G-Protein-Coupled Receptors; Genetic Transcription; Genetically Engineered Mouse; Goals; HSP 90 inhibition; High Density Lipoproteins; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Immune; Immune system; Immunologics; Impairment; Indoles; Induction of Apoptosis; Intestines; KRAS2 gene; Ketone Bodies; Knock-out; Lamina Propria; Lead; Link; Liver; Low-Density Lipoproteins; MDM2 gene; Maintenance; Malignant Neoplasms; Mediator; Molecular; Molecular Chaperones; Molecular Target; Mus; Mutation; Nicotinic Acids; Oncology; Organ; Organism; Pathway interactions; Persons; Pharmaceutical Preparations; Physiological; Play; Prevention; Prevention strategy; Process; Proteins; Receptor Activation; Regulation; Regulatory T-Lymphocyte; Rejuvenation; Role; SIRT1 gene; Side; Signal Transduction; Site; Survival Rate; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Time; Tumor Immunity; Tumor Suppressor Proteins; Vitamins; Woman; Xenobiotics; beta-Hydroxybutyrate; cancer cell; cancer therapy; chemical carcinogen; colon bacteria; colon cancer prevention; colon cancer treatment; commensal bacteria; dietary carcinogenesis; environmental chemical; functional disability; ketogenesis; ketogentic; luminal membrane; men; mutant; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; prevent; receptor; therapeutic development; tumor

Project Summary: Chemical carcinogens and xenobiotics in the diet play a significant role in colon cancer (CC) formation. The intestinal tract, including the colon, is often the first site that is exposed to these carcinogens and xenobiotics. CC is a common malignancy in men and women, and p53 mutation (p53D) or inactivation is observed in ~60% of CC and ~90% of all human cancers. As such, the development of therapeutic strategies that will rejuvenate wild-type (WT) p53 function or target p53D should have profound implications in the prevention and treatment of CC. Similarly, a high frequency (40-60%) of KRAS mutation (KRASD) is observed in organisms exposed to environmental chemical contaminants, and ~40-45% of CC is associated with KRASD. We found a reciprocal association between GPR109A expression and KRASD CC. GPR109A is a Gai-coupled receptor for the bacterial fermentation product butyrate (BTR), the ketone body b-hydroxybutyrate (bHB), and the vitamin Niacin (NA). About 85% of CC shows a reduced expression of GPR109A. GPR109A agonists NA is the precursor of NAD+ and p53 is an NAD+-dependent molecule and NA deficiency impairs p53 function. Therefore, GPR109A could be the molecular target of KRAsD and it plays an important role in the regulation of p53 signaling. Pharmacologic doses of NA, a vitamin and also an FDA-approved drug for dyslipidemia, is taken by millions of Americans. Though the role of NA in decreasing LDL and increasing HDL is well recognized, little is known about its anti-tumor potential. Similarly, the link between commensal bacteria and CC prevention is known for a long time, but the mechanisms underlying this link are not well understood. BTR, the prominent bacterial metabolite in the colon, is the endogenous agonist for GPR109A in colonic epithelia. bHB is the natural agonist for GPR109A in immune cells present in the lamina propria and this agonist is synthesized in colonic epithelia using the bacterial metabolite BTR via ketogenesis. This highlights the biological significance of the colon as a ketogenic organ. In addition, commensal bacteria control GPR109A expression and ketogenesis in the colon via their xenobiotic metabolites (butyrate, indole derivatives, 1,3-diaminopropane, and reuterin). This offers a novel molecular link between commensal bacteria and CC prevention. Our central hypothesis is that activation of GPR109A in colonic epithelia and immune cells lead to sustained activation of p53 and anti- tumor immunity. We will test this hypothesis with three specific aims: (Aim 1) Determine the role of the GPR109A- p53 axis in KRASD, chemical, and dietary carcinogen-induced CC; (Aim 2) Elucidate the molecular mechanism(s) of GPR109A agonists-induced p53 activation and test if GPR109A agonists can be used as novel therapeutic drugs to target p53D CC; and (Aim 3) Demonstrate that commensal bacterial metabolites maintain WTp53 function and prevent the immune system from undue activation in colon via GPR109A with an obligatory involvement of colonic ketogenesis. These studies will involve the use of genetically modified mouse lines with colon-specific deletion of not only Gpr109a and p53, but also the rate-limiting enzyme in ketogenesis, Hmgcs2.

项目摘要：饮食中的化学致癌物和异生物质在结肠癌 (CC) 中发挥重要作用 形成。肠道，包括结肠，通常是最先接触这些致癌物质的部位， 异生素。 CC是男性和女性常见的恶性肿瘤，p53突变（p53D）或失活是 在约 60% 的 CC 和约 90% 的所有人类癌症中观察到。因此，治疗策略的发展 这将恢复野生型 (WT) p53 功能或靶向 p53D 应该对 CC的预防和治疗。同样，观察到 KRAS 突变 (KRASD) 的频率较高 (40-60%) 在暴露于环境化学污染物的生物体中，约 40-45% 的 CC 与 KRASD 有关。 我们发现 GPR109A 表达与 KRASD CC 之间存在相互关联。 GPR109A 是 Gai 耦合 细菌发酵产物丁酸（BTR）、酮体b-羟基丁酸（bHB）的受体，以及 维生素烟酸（NA）。约 85% 的 CC 显示 GPR109A 表达减少。 GPR109A 激动剂 NA 是 NAD+ 和 p53 的前体是 NAD+ 依赖性分子，NA 缺乏会损害 p53 功能。 因此，GPR109A可能是KRAsD的分子靶点，在KRAsD的形成中发挥着重要作用。 p53 信号传导的调节。 NA（一种维生素，也是 FDA 批准的药物）的药理学剂量 数百万美国人患有血脂异常。尽管 NA 在降低 LDL 和增加 HDL 方面的作用是 其抗肿瘤潜力已广为人知，但人们对其却知之甚少。同样，共生细菌和 CC 预防早已为人所知，但这种联系背后的机制尚不清楚。贝特瑞, 结肠中重要的细菌代谢产物，是结肠上皮细胞中 GPR109A 的内源性激动剂。乙肝 是固有层免疫细胞中 GPR109A 的天然激动剂，该激动剂是合成的 在结肠上皮细胞中，通过生酮作用使用细菌代谢物 BTR。这凸显了生物学意义 结肠作为生酮器官。此外，共生细菌控制 GPR109A 表达和生酮作用 在结肠中通过其异生代谢物（丁酸盐、吲哚衍生物、1,3-二氨基丙烷和罗伊氏菌）。 这在共生细菌和 CC 预防之间提供了一种新颖的分子联系。我们的中心假设是 结肠上皮和免疫细胞中 GPR109A 的激活导致 p53 和抗- 肿瘤免疫。我们将通过三个具体目标来检验这一假设：（目标 1）确定 GPR109A- 的作用 KRASD、化学和饮食致癌物诱发的 CC 中的 p53 轴； （目标 2）阐明分子 GPR109A 激动剂诱导 p53 激活的机制并测试 GPR109A 激动剂是否可以用作新型药物 靶向 p53D CC 的治疗药物； （目标 3）证明共生细菌代谢物维持 WTp53 通过 GPR109A 发挥作用并防止结肠中免疫系统过度激活 参与结肠生酮。这些研究将涉及使用转基因小鼠品系 结肠特异性删除不仅包括 Gpr109a 和 p53，还包括生酮限速酶 Hmgcs2。