Glutaredoxin, Glutathione Metabolism and Lung Cancer

谷氧还蛋白、谷胱甘肽代谢与肺癌

• 批准号: 10657945
• 负责人: Yvonne M. W. Janssen-Heininger
• 金额: $ 53.51万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-10 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657945
• 关键词: Ablation; Address; Adenoviruses; Amino Acids; Antioxidants; Attenuated; Binding; Biochemistry; Breeding; Cessation of life; Cisplatin; Clinical; Cysteine; Cystine; Dependovirus; Development; Enterobacteria phage P1 Cre recombinase; Environment; Glutamates; Glutathione; Glutathione Metabolism Pathway; Growth; Homeostasis; Human; Immune checkpoint inhibitor; In Vitro; KRAS2 gene; KRASG12D; Link; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Mus; NADP; Oncogenic; Organoids; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Property; Protein S; Proteins; Proteomics; Refractory; Regimen; Resistance; Role; Signal Transduction; Structure; Sulfhydryl Compounds; System; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Tumor Burden; Ubiquitination; Xenograft procedure; antiporter; combat; glutaredoxin; glutaredoxin 2; human subject; insight; lung cancer cell; lung tumorigenesis; mutant; neoplastic cell; novel therapeutic intervention; ovarian neoplasm; penicillamine-glutathione mixed disulfide; preclinical development; prevent; side effect; standard of care; tumor; tumor growth; tumorigenesis; tumorigenic; ubiquitin isopeptidase

PROJECT SUMMARY Glutathione (GSH) is a small thiol antioxidant that is critical in maintaining redox homeostasis, and increases in glutathione occur in KRAS-mutant lung adenocarcinoma. Glutathione can also lead to S-glutathionylation (PSSG), the conjugation of GSH to reactive cysteines in proteins, which can be reversed by the de- glutathionylase, glutaredoxin (GLRX). While the glutaredoxin/PSSG system has emerged as a key regulator of redox signaling, little is known about its disruption in lung adenocarcinoma (LUAD). We have made the exciting discovery that GLRX expression is decreased in human LUAD and that KrasG12D-induced lung tumorigenesis is enhanced in mice lacking Glrx. In a redox proteomics screen we revealed increases in S-glutathionylation of ovarian tumor deubiquitinase, OTUB1, which was recently identified as a regulator of System XC-. System XC- is a cystine/glutamate antiporter that exports glutamate and imports cystine, which is in turn reduced intracellularly to cysteine, the rate limiting amino acid in glutathione synthesis. System XC- is composed of SLC7A11 and SLC3A2. OTUB1 binds to SLC7A11 to prevent its ubiquitination and proteasomal degradation. We have made the exciting discovery that S-glutathionylation of OTUB1 is important in the stabilization of SLC7A11, leading to increases in GSH. Compared to adjacent control tissue, expression of OTUB1 and SLC7A11 are increased in LUAD. These exciting findings led us to hypothesize that decreases in glutaredoxin expression in mutant KRAS-driven lung adenocarcinoma cause increases in system XC- activity through the S- glutathionylation of ovarian tumor deubiquitinase 1 (OTUB1), augmenting glutathione and promoting survival of lung cancer cells. Furthermore, we hypothesize that avenues to augment glutaredoxin will diminish GSH levels leading to increased potency of cisplatin-induced killing of lung cancer cells. In Specific Aim 1 we will determine whether GLRX status controls KrasG12D-induced tumorigenesis. Specific Aim 2 proposes to address the importance of OTUB1 S-glutathionylation and System XC- in the augmentation of GSH in KrasG12D- induced tumors while in Specific Aim 3 we aim to address the impact of AAV-mediated transduction of GLRX on cisplatin-induced tumor killing in primary LUAD tumor organoids and KrasG12D-driven tumors in mice. Completion of this proposal will provide new insights into the role of the GLRX-protein S-glutathionylation redox system in the pathogenesis of LUAD and offers a rationale for augmenting GLRX in lung tumors in order to promote killing. The pharmaceutical development of GLRX has the potential to offer new therapeutic strategies to combat LUAD, in combination with standard of care therapy.

项目总结