The kynurenine-AHR pathway in biomass production

项目总结 增加大分子的摄取和合成对于维持高增殖性的需求是必不可少的 癌细胞。因此，开发限制特定于肿瘤的生物量产生的方法可能会有 对癌症治疗的深远影响。而开创性的研究表明，普遍的癌基因 MYC促进癌细胞中蛋白质的合成，但我们对MYC是如何在分子上 控制致癌转化过程中的翻译。我们发现转录因子芳香烃 受体(AHR)及其配体犬尿氨酸是氨基酸色氨酸的副产物，由MYC诱导。 结肠癌细胞。我们的初步结果表明，AHR对于相关基因的表达是必要的。 在核糖体的生物发生和增殖细胞中的蛋白质合成。我们的假设是AHR感觉和 对色氨酸衍生的犬尿氨酸的反应是通过移位到细胞核并诱导转录 在结肠癌细胞中介导核糖体生物发生和翻译的基因。目标1将直接测试 利用人结肠等基因系中的基因沉默，研究AHR在结肠癌细胞蛋白质合成中的作用 上皮细胞和小鼠器官细胞进展为结肠癌。目标2将确定以下贡献 犬尿氨酸对AHR调节的蛋白质合成和细胞增殖的影响 犬尿氨酸可促进AHR靶基因的表达、蛋白质合成和生长。我们将利用AHR淘汰赛 细胞和动物，以及阻止犬尿氨酸与AHR结合的竞争性抑制剂，以定义AHR- 由犬尿氨酸调节的特定功能。目标3将直接测试色氨酸代谢的重要性 产生犬尿氨酸和调节结肠细胞增殖的酶。我们将确定其影响 敲除或敲除犬尿氨酸途径中的酶，以确定它们对AHR的需求 结肠癌细胞和有机物的活性、蛋白质合成和增殖。这项研究有可能 明确犬尿氨酸-AHR途径在推动生物量增加和 结肠癌中的细胞增殖。此外，这项研究还将扩大对犬尿氨酸作用的理解。 作为一种新陈代谢物质。我们的发现可能成为开发新的限制方法的基础 犬尿氨酸产生和AHR活性作为治疗MYC依赖肿瘤的手段。

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.