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Metabolic reprogramming in liver cancer cells by a novel tumor suppressor

新型肿瘤抑制因子对肝癌细胞的代谢重编程

基本信息

批准号：
9128584
负责人：
Yuxia Zhang
金额：
$ 11.82万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-18 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9128584
关键词：
Acetyl Coenzyme A Affect Apoptosis Cancer Biology Cell Proliferation Citric Acid Cycle DNA DNA Modification Methylases Deacetylase Development Development Plans Diagnosis Ensure Gene Expression Genes Glucose Growth Health HepG2 Human Hypermethylation In Vitro Isoenzymes Lead Liver Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Mediating Mentors Metabolic Metabolic Control Metabolism Mitochondria Molecular Molecular Target Mus NADH Nuclear Receptors Nutrient Outcome Study PDH kinase Pathway interactions Phosphorylation Physiological Play Prevention strategy Primary carcinoma of the liver cells Process Productivity Public Health RNA immunoprecipitation sequencing Repression Research Role Signal Transduction Staging Survival Rate Testing Therapeutic Training Transcription Repressor/Corepressor Tumor Suppressor Genes Tumor Suppressor Proteins Work Xenograft procedure anticancer research cancer cell career career development cell growth collaborative environment experience genome-wide glucose metabolism hepatocellular carcinoma cell line in vivo insight lipid biosynthesis lipid metabolism liver cell proliferation mitochondrial metabolism neoplastic cell novel overexpression oxidation post-doctoral training programs promoter pyruvate dehydrogenase sensor treatment strategy tumor tumor growth tumor metabolism tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has one of the worst 1-year survival rates of any cancer. There is a major need for understanding of the molecular mechanisms leading to HCC. Identifying new tumor suppressor genes that regulate the development of HCC could lead to new treatments or prevention strategies for this unsolved public health problem. The central hypothesis is that PDK4 is a novel tumor suppressor gene for HCC. PDK4 is silenced in HCC and inactivation of PDK4 signaling modulates the metabolic fate of glucose to favor HCC development via crosstalk with both AMPK pathway and the NAD+-dependent deacetylase SIRT1 pathway. The hypothesis is supported by our preliminary results: 1) PDK4 is downregulated in human HCC; 2) The promoter of PDK4 gene is hypermethylated in human HCC cell line HepG2; 3) Overexpression of PDK4 decreases intracellular ATP pools and NAD+/NADH ratios; 4) Overexpression of PDK4 activates AMPK �2 and SIRT1 gene expression; 5) PDK4 suppresses HCC cell growth in vitro and inhibits Xenograft tumor growth in vivo; 6) PDK4 is hypermethylated in Shp-/- mouse livers that develop spontaneous HCC. PDK4 catalyzes the phosphorylation and inactivation of mitochondrial pyruvate dehydrogenase (PDH) which plays a central role in regulating glucose metabolism by producing Acetyl-CoA for oxidation in the Krebs cycle. Elucidating the function of PDK4 in the development of HCC will be the main focus of this application. We will test the hypothesis through two specific aims: 1) Characterize how PDK4 alters metabolic reprogramming in liver cancer cells; 2) Define the molecular mechanisms and physiological role of PDK4 in regulating HCC growth. Dr. Zhang has successfully completed 5 years post-doctoral training with a track record of productivity, and she is at the critical transiion point toward independence. Dr. Zhang has a strong background in nuclear receptor and molecular cancer research that will be further augmented by the described program in cancer metabolism. She will be guided by a well-matched mentoring committee of experts in relevant fields: Dr. Li Wang in nuclear receptors and lipid metabolism in liver cancer, Dr. Don Ayer in cancer cell glucose metabolism and Dr. Jared Rutter in mitochondrial metabolism. Additional career development advisors including Drs. E. Dale Abel, Curt Hagedorn, and Melinda Angus-Hill will provide objective reviews of her progress and ensure that her professional and scientific development activities are on track. The training in the career development plan will enable her to continue identifying challenging and relevant research questions and provide a collaborative working environment with experienced experts. This will facilitate the growth of an independent career in cancer biology with an emphasis on cancer metabolism.

描述（由申请人提供）：肝细胞癌（HCC）是世界上最常见的癌症之一，也是所有癌症中1年生存率最差的癌症之一。目前迫切需要了解导致HCC的分子机制。发现调节HCC发展的新肿瘤抑制基因可能为这一未解决的公共卫生问题带来新的治疗或预防策略。中心假设是PDK4是HCC的一种新的肿瘤抑制基因。PDK4在HCC中沉默，PDK4信号的失活通过与AMPK途径和NAD+依赖性去乙酰化酶SIRT1途径的串话调节葡萄糖的代谢命运，促进HCC的发展。我们的初步结果支持了这一假设：1)PDK4在人类HCC中下调；2)人肝癌细胞系HepG2中PDK4基因启动子高甲基化；3) PDK4过表达降低细胞内ATP池和NAD+/NADH比值；4) PDK4过表达激活AMPK - 2和SIRT1基因表达；5) PDK4在体外抑制肝癌细胞生长，在体内抑制异种移植物肿瘤生长；6) PDK4在发生自发性HCC的Shp-/-小鼠肝脏中高甲基化。PDK4催化线粒体丙酮酸脱氢酶（PDH）的磷酸化和失活，PDH通过在克雷伯循环中产生用于氧化的乙酰辅酶a在调节葡萄糖代谢中起核心作用。阐明PDK4在HCC发展中的功能将是本应用的主要重点。我们将通过两个具体目标来验证这一假设：1)表征PDK4如何改变肝癌细胞的代谢重编程；2)明确PDK4调控HCC生长的分子机制及生理作用。张博士已经成功完成了5年的博士后培训，并拥有良好的生产力记录，她正处于走向独立的关键转折点。张博士在核受体和分子癌症研究方面有很强的背景，并将通过所述的癌症代谢项目进一步增强。她将受到相关领域专家组成的指导委员会的指导：Li Wang博士负责肝癌核受体和脂质代谢，Don Ayer博士负责癌细胞葡萄糖代谢，Jared Rutter博士负责线粒体代谢。其他职业发展顾问包括博士。E. Dale Abel， Curt Hagedorn和Melinda Angus-Hill将对她的进展进行客观的评估，并确保她的专业和科学