Modifier of Cancer Sensitivity to Statins

癌症对他汀类药物敏感性的调节剂

• 批准号: 9251790
• 负责人: David Mu
• 金额: $ 19.12万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251790
• 关键词: 14q13; ATP binding cassette transporter 1; Alpha Cell; Arachidonic Acids; Biological Models; Breast Cancer Cell; Cancer Biology; Cell Survival; Cells; Cholesterol; Cholesterol Homeostasis; Clinical Research; Data; Diagnosis; Drops; Gene Expression; Gene Expression Profiling; Genes; Growth; Human; Introns; Link; Liver; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Metabolism; MicroRNAs; Modeling; Oncogenes; Outcome; Outcome Study; Pathologist; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Plant Roots; Polyunsaturated Fatty Acids; Proteins; Publishing; Recurrence; Regulation; Research; Role; SRE-2 binding protein; Signal Transduction; Site; Somatic Cell; TP53 gene; Time; Translational Research; Up-Regulation; Xenograft procedure; base; cancer cell; cancer type; cholesterol biosynthesis; cytotoxicity; efficacy testing; improved; inhibitor/antagonist; knock-down; lung xenograft; malignant phenotype; mevalonate; mutant; novel; overexpression; prostate cancer cell; public health relevance; therapeutic evaluation; thyroid transcription factor 1; transcription factor; tumor; uptake

 DESCRIPTION (provided by applicant): We have recently discovered an unexpected connection between a critical lung cancer gene termed thyroid transcription factor 1 (TTF-1 also known as NKX2-1) and cholesterol metabolism. By searching for downstream target microRNAs of TTF-1, we found that TTF-1 upregulates miR-33a which is known to be critical for cholesterol regulation by suppressing ATP-binding cassette transporter 1 (ABCA1) and its associated cholesterol efflux function. Thus, we set out to demonstrate that a higher TTF-1 expression would presumably inhibit cholesterol efflux and raise intracellular cholesterol level. Surprisingly in our preliminary studies we found that raising TTF-1 expression actually lowers intracellular cholesterol level, which we believe is attributed to our discovery that TTF-1 directly transactivates ABCA1. In view of the fact that cholesterol is essential for cell viability, we surmised that lung cancer cells primed with a TTF-1-driven decrease of cholesterol would be sensitized to cholesterol biosynthesis inhibitors. Indeed, enforced expression of TTF-1 in human lung cancer cells enhanced cellular sensitivity to statins, a frequently prescribed medication to lower systemic cholesterol. Under Aim 1, we plan to comprehensively characterize the functional requirement of ABCA1 for the enhanced statin sensitivity of cells with TTF-1 overexpression. Subsequently, under Aim 2 we wish to use both orthotopic and anonymized patient-derived lung cancer model systems to test the efficacy of statins against TTF-1+ lung adenocarcinomas. Given the fact that pathologists routinely interrogate human lung cancers for TTF-1 immunopositivity to guide diagnosis and the prevalent use of statins, the outcome of this study will inspire translational and clinical research to improve lung cancer management.