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Investigation of NRF2-Dependent Metabolic Liabilities

NRF2 依赖性代谢负担的研究

基本信息

批准号：
10411427
负责人：
Gina Marie DeNicola
金额：
$ 1.06万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411427
关键词：
Agar Amino Acids Antioxidants Biology CRISPR/Cas technology Cancer Center Cancer Model Cancer Patient Cancer cell line Cells Cysteine Cysteine Metabolism Pathway Cysteine dioxygenase Cystine Data Engineering Enzymes Genetic Engineering Genetically Engineered Mouse Genets Glutamates Glutathione Glycine Goals Growth Human Investigation Knock-in Mouse Lead Lung Adenocarcinoma Lung Capacity Lung Neoplasms Maintenance Malignant neoplasm of lung Mediating Metabolic Metabolic Control Metabolism Methylation Modeling Mutant Strains Mice Mutation Nature Non-Small-Cell Lung Carcinoma Outcome Oxidation-Reduction Oxidative Stress Oxides Pathway interactions Patients Positioning Attribute Process Production Proteins Role Sampling Specimen Sulfites Sulfur System TXN gene Taurine Testing Therapeutic Intervention Toxic effect Work Xenograft Model cancer therapy cysteine sulfinate disulfide bond epigenetic silencing hypotaurine in vivo Model lung cancer cell lung tumorigenesis metabolomics mouse model mutant neoplastic cell novel protein expression response restoration targeted treatment transcription factor tumor tumor initiation tumorigenesis uptake

项目摘要

Metabolic reprogramming occurs during tumorigenesis and holds promise for cancer therapy. However, the underlying mechanisms that control these metabolic alterations and their contribution to tumor maintenance are generally lacking. Mutations in NRF2 and its negative regulator KEAP1 are found in 15-34% of non-small cell lung cancer (NSCLC) and lead to constitutive NRF2 activity. Many NRF2-regulated processes center on the production and utilization of the antioxidant glutathione, which is synthesized from the amino acids cysteine, glycine and glutamate. In our previous work, we found that glutathione synthesis was critical for the pro-proliferative effects of NRF2 during tumor initiation. Furthermore, we found that NRF2 promotes metabolic rewiring to increase glycine availability to support glutathione synthesis. To define how constitutive NRF2 activity induces metabolic reprogramming to support GSH synthesis, we generated genetically engineered, conditional knock-in mouse models of the cancer mutations NRF2D29H and KEAP1R554Q. Our preliminary analysis of NRF2-regulated metabolism indicates that cysteine dioxygenase (CDO1) limits glutathione production by NRF2, produces toxic byproducts, and is silenced during tumorigenesis. We have established a metabolomics platform for the analysis of sulfur-containing metabolites, and a genetically engineered NRF2 and KEAP1 mutant lung cancer mouse models for in vivo studies and are now poised to define the tumor suppressive role of CDO1 and its metabolites during lung tumorigenesis. In Aim 1 we will examine the whether CDO1 antagonizes the NRF2-regulated antioxidant response by depleting cysteine. In Aim 2 we will examine the selective toxicity of CDO1 expression to cells with NRF2 activity due to toxic byproduct production. In Aim 3 we will examine whether CDO1 loss promotes lung tumorigenesis using our genetically engineered KEAP1 and NRF2 mutant mouse lung tumor models and patient tumor samples. The ultimate goal and the overall impact of this project are to characterize CDO1 as a novel metabolic liability for tumors with NRF2/KEAP1 mutations in order to define opportunities for therapeutic intervention for patients with these mutations, which currently lack targeted therapy.

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