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NRF2-dependent redox signaling in pancreatic cancer

胰腺癌中 NRF2 依赖性氧化还原信号传导

基本信息

批准号：
10348724
负责人：
Iok In Christine Chio
金额：
$ 36.63万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-04 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10348724
关键词：
Ablation Amino Acids Biochemical Biochemical Genetics Biological Assay Biology ChIP-seq Cysteine Cytostatics DNA DNA Damage Development Elongation Factor Enzymes Genes Genetic Genetic Transcription Genetically Engineered Mouse Glycolysis Growth Homeostasis Human Impairment In Vitro KRAS oncogenesis KRAS2 gene Lipids Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Methionine Modification Mus Mutate Mutation Natural Killer Cells Oncogenes Organoids Oxidation-Reduction Oxides Pancreatic Ductal Adenocarcinoma Pancreatic duct Pathogenesis Post-Translational Protein Processing Process Prognosis Protein Biosynthesis Proteins Proteome Reactive Oxygen Species Regulation Resistance Ribosomes Role Signal Transduction Stage at Diagnosis Sulfur Testing Transcript Translations Transplantation Up-Regulation Western Blotting advanced disease base biochemical tools cancer cell cytotoxic cytotoxicity effective therapy fitness genetic approach in vivo interest macromolecule mouse model mutant neoplastic cell oxidation oxidative DNA damage pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic tumorigenesis ribosome profiling therapeutic target transcription factor transcriptome sequencing tumor tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy that remains largely incurable. The dismal prognosis of PDA reflects its advanced disease stage at diagnosis and its profound resistance to existing therapies. The KRAS oncogene is mutated in 95% of PDAs and acts as a potent driver of PDA growth and maintenance. Oncogenic KRAS induces transcriptional upregulation of NFE2L2, which encodes the NRF2 transcription factor, a master regulator of redox homeostasis that protects cells from the cytotoxic/cytostatic effects of reactive oxygen species (ROS). Importantly, we found that genetic ablation of NRF2 suppresses the growth of pancreatic cancer cells both in vitro and in vivo (2). Although elevated levels of ROS are generally believed to induce cytotoxicity through irreversible damage to macromolecules, particularly DNA and lipids, we discovered that genetic ablation of NRF2 did not lead to DNA or lipid damage (2). Instead, both protein synthesis and tumor cell fitness were compromised as a consequence of reversible and selective oxidation of cysteine residues on key regulators of protein synthesis (2). Based on these observations, we hypothesize that NRF2 promotes pancreatic tumorigenesis through its ability to regulate oxidative post-translational modifications (oxPTM). Herein, we propose to elucidate the mechanisms underlying this process, determine the functions of redox control in PDA, and identify potential therapeutic targets. To this end, we will use ChIP- seq and RNAseq to identify direct Nrf2 targeting genes that govern cysteine oxidative modification (Aim 1). In addition, we will use a variety of biochemical approaches to delineate the mechanisms through which cysteine oxidation contributes to protein synthesis in PDA. We will further define transcript-specific effects of redox- dependent translation regulation through ribosome profiling (Aim 2). In addition to cysteine, we recently discovered that perturbation of NRF2 activity also leads to the reversible oxidation of the other sulfur-containing amino acid, methionine. Various biochemical and genetic approaches will be taken to assess the functional role of methionine oxidation in pancreatic tumorigenesis (Aim 3). We anticipate that our results will explain fundamental aspects of redox homeostasis in PDA and will inform the development of more effective therapies for pancreatic cancer and potentially other KRAS-driven malignancies.

项目总结