Investigating GSTP1 as a novel regulator of the cysteine redoxome in breast cancer and maker of vulnerability to redox-based therapy

研究 GSTP1 作为乳腺癌中半胱氨酸氧化还原体的新型调节剂以及氧化还原治疗脆弱性的制造者

• 批准号: 10576645
• 负责人: Jason M. Held
• 金额: $ 18.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-12 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10576645
• 关键词: Affect; Antioxidants; Biological; Biological Assay; Biological Markers; Biology; Breast Cancer Cell; Breast Cancer cell line; Cancer Patient; Cancer cell line; Cell Line; Cells; Cessation of life; Chemistry; Clinic; Clinical; Clinical Trials; Complement; Complex; Cysteine; Disease; Electrons; Endocrine; Enzymes; Evaluation; Glutathione; Growth; In Vitro; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of prostate; Metabolic; Modality; Modeling; Molecular; NADPH Oxidase; Neoplasm Metastasis; Oncogenic; Organoids; Oxidation-Reduction; Pathway interactions; Patients; Phenotype; Proteins; Proteome; Regulation; Relapse; Reporting; Repression; Resistance; Role; Sentinel; Signal Transduction; Signaling Protein; Techniques; Testing; Therapeutic; Treatment Efficacy; Up-Regulation; acetovanillone; acquired treatment resistance; anti-cancer; cancer subtypes; cancer type; candidate identification; candidate marker; cysteinesulfenic acid; disulfide bond; ebselen; epigenetic regulation; epigenetic silencing; glutathione S-transferase pi; in vivo; inhibitor; insight; interest; mRNA Expression; malignant breast neoplasm; molecular marker; novel; novel marker; overexpression; oxidation; patient derived xenograft model; pharmacodynamic biomarker; predictive marker; prognostic; protein expression; protein function; protein protein interaction; protein structure; sensor; small molecule; transcriptomics; tumor; tumorigenesis

Project Summary Glutathione S-transferase Pi 1 (GSTP1) is an enzyme that conjugates glutathione to small molecule electrophiles. GSTP1 has been implicated in promoting the growth of many cancer types where GSTP1 overexpression is proposed to promote metabolic re-wiring or sequester cancer-related signaling proteins through protein-protein interactions. In contrast to the modest upregulation of GSTP1 in cancer reported by these studies, our systematic evaluation of cancer cell lines, patient-derived xenografts, and patient tumors finds that GSTP1 expression is uniquely and dramatically silenced by many orders of magnitude in luminal breast cancer, going from one of the most abundant cellular proteins to barely express. Her2 positive (Her2+) breast cancers have a bimodal GSTP1 expression distribution, with a significant proportion also silencing GSTP1. Decreased GSTP1 expression in breast cancer allowed us to discover a novel, non-canonical regulatory function of GSTP1: re-directing the flux of cysteine oxidation to structurally remodel the proteome via allosteric disulfide bonds. These changes are critical for breast cancer transformation since re-expression of GSTP1 and inhibition of redox signaling decreases the transformation capacity of GSTP1-silenced breast cancer cells. This proposal focuses on two Specific Aims. First, is GSTP1 silencing a therapeutic vulnerability in BRCA? Second, what are the molecular and redoxomic consequences of GSTP1 silencing? Together, these Aims will provide new mechanistic insight into how GSTP1 expression drives redox signaling in breast cancer and determine if GSTP1 silencing is a therapeutically actionable vulnerability.

项目总结