The kynurenine-AHR pathway in biomass production

生物质生产中的犬尿氨酸-AHR 途径

• 批准号: 10835135
• 负责人: Maralice Conacci-Sorrell
• 金额: $ 8.29万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10835135
• 关键词: APC gene; Amino Acids; Animals; Aryl Hydrocarbon Receptor; Automobile Driving; Binding; Biogenesis; Biomass; Cancer Cell Growth; Cell Nucleus; Cell Proliferation; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Colon; Colon Carcinoma; Development; Enzymes; Epithelial Cells; Gene Expression; Genes; Genetic; Genetic Transcription; Growth; Human; In Vitro; Knock-out; Kynurenine; Label; Ligands; MYC gene; Maintenance; Malignant Neoplasms; Manuscripts; Mediating; Metabolic; Metabolic Pathway; Modeling; Molecular; Monitor; Mus; Oncogenes; Oncogenic; Organoids; Pathway interactions; Physiological; Play; Preparation; Production; Proliferating; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-myc; Regulation; Research; Ribosomes; Role; Seminal; T-Lymphocyte; Testing; Therapeutic Intervention; Translations; Tryptophan; cancer cell; cancer therapy; cell growth; colon growth; in vivo; inhibitor; knock-down; macromolecule; novel; novel strategies; nutrient absorption; prevent; transcription factor; tumor; tumor growth; tumor metabolism; uptake

PROJECT SUMMARY Increased uptake and synthesis of macromolecules is essential to sustain the demands of hyperproliferative cancer cells. Therefore, developing approaches to limit biomass production specifically in tumors could have profound implications for cancer treatment. While seminal studies have shown that the universal oncogene MYC promotes protein synthesis in cancer cells, there is still a gap in our understanding of how MYC molecularly controls translation during oncogenic transformation. We found that the transcription factor aryl hydrocarbon receptor (AHR) and its ligand kynurenine, a byproduct of the amino acid tryptophan, are induced by MYC in colon cancer cells. Our preliminary results indicate that AHR is necessary for the expression of genes involved in ribosomal biogenesis and protein synthesis in proliferating cells. Our hypothesis is that AHR senses and responds to tryptophan-derived kynurenine by translocating into the nucleus and inducing the transcription of genes that mediate ribosome biogenesis and translation in colon cancer cells. Aim 1 will directly test the role of AHR in protein synthesis in colon cancer cells, using genetic silencing in isogenic lines of human colonic epithelial cells and of mouse organoids progressed to colon cancer. Aim 2 will establish the contribution of kynurenine to AHR-regulated protein synthesis and cell proliferation by examining the requirement for kynurenine for the expression of AHR target genes, protein synthesis, and growth. We will utilize AHR knockout cells and animals and a competitive inhibitor that prevents the binding of kynurenine to AHR to define AHR- specific functions regulated by kynurenine. Aim 3 will directly test the importance of tryptophan-metabolizing enzymes in generating kynurenine and in regulating proliferation of colonic cells. We will determine the effects of knocking down or knocking out enzymes in the kynurenine pathway to define their requirement for AHR activity, protein synthesis, and proliferation of colon cancer cells and organoids. This study has the potential to define a direct physiological role for the kynurenine-AHR pathway in driving increased biomass production and cell proliferation in colon cancer. Moreover, this study will broaden the understanding of the role of kynurenine as an oncometabolite. Our findings could become the basis for the development of novel approaches to limit kynurenine production and AHR activity as a means to treat MYC-dependent tumors.

项目摘要 大分子的摄取和合成对于维持超增殖的需求至关重要 癌细胞。因此，开发的方法以限制肿瘤中专门限制生物量的生产 对癌症治疗的深刻影响。开创性研究表明通用癌基因 MYC促进癌细胞中的蛋白质合成，我们对MYC分子的理解仍然存在差距 控制致癌过程中的翻译。我们发现转录因子芳基烃 受体（AHR）及其配体kynurenine是氨基酸色氨酸的副产品，由Myc诱导 结肠癌细胞。我们的初步结果表明，AHR对于所涉及的基因表达是必要的 在增殖细胞中的核糖体生物发生和蛋白质合成中。我们的假设是AHR感官和 通过转移到细胞核并诱导转录的转录来应对色氨酸衍生的kynurenine 介导结肠癌细胞中核糖体生物发生和翻译的基因。 AIM 1将直接测试 在结肠癌细胞中蛋白质合成中的AHR，使用人类结肠的同源线中的遗传沉默 上皮细胞和小鼠类器官发展为结肠癌。 AIM 2将确定 Kynurenine通过检查对AHR调节的蛋白质合成和细胞增殖，通过检查对 Kynurenine表达AHR靶基因，蛋白质合成和生长。我们将利用AHR淘汰 细胞和动物以及竞争性抑制剂，可防止kynurenine与AHR结合以定义AHR- 由kynurenine调节的特定功能。 AIM 3将直接测试色氨酸代谢的重要性 酶产生kynurenine和调节结肠细胞的增殖。我们将确定效果 敲门或敲除kynurenine途径中的酶以定义其对AHR的要求 结肠癌细胞和器官的活性，蛋白质合成和增殖。这项研究有可能 定义kynurenine-ahr途径在推动生物量产生和 结肠癌的细胞增殖。此外，这项研究将扩大对Kynurenine的作用的理解 作为oncometabolite。我们的发现可能成为开发新方法以限制的基础 Kynurenine的产生和AHR活性是治疗依赖MYC的肿瘤的一种手段。