(PQB4)SIRT6 Modulates Cancer Metabolism During Aging

(PQB4)SIRT6 调节衰老过程中的癌症代谢

• 批准号: 8850410
• 负责人: Raul Mostoslavsky
• 金额: $ 21.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850410
• 关键词: Aerobic; Age; Aging; Aging-Related Process; Animals; Automobile Driving; Cause of Death; Cell Respiration; Cells; Colorectal Cancer; Control Animal; Data Set; Deacetylase; Dependency; Development; Dichloroacetate; Disease; Disease Outcome; Elderly; Energy Metabolism; Enzymes; Exhibits; Family; Future; Genetic Transcription; Genetically Engineered Mouse; Glycolysis; Grant; Growth; Health; Heart Diseases; Histone Deacetylase; Histones; Human; Incidence; Link; Longevity; Malignant Neoplasms; Mammals; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Mutation; Normal tissue morphology; Oncogenic; Pathway interactions; Patients; Phenotype; Physiological; Population; Production; Proteins; Risk; Role; Staging; Stress; Therapeutic; Tissues; Tumor Suppressor Proteins; Warburg Effect; aerobic glycolysis; aging population; base; blood glucose regulation; cancer cell; cancer type; cohort; colon cancer patients; design; glucose metabolism; glucose uptake; inhibitor/antagonist; middle age; mortality; mouse model; overexpression; protein expression; response; sugar; tumor; tumor growth; tumor metabolism; tumorigenesis

DESCRIPTION (provided by applicant): Aging is associated with a decline in physiological functions and a major incidence of several diseases. Among them, the risk of suffering from cancer dramatically increases with age. In fact, together with heart diseases, it represents the first cause of death in elder people. Besides the gradual accumulation of mutations with age, very little is known about the molecular mechanisms involved in the increased cancer incidence during aging. A prominent feature of cancer cells is their increased glucose uptake and reliance on aerobic glycolytic metabolism, a phenomenon described by Otto Warburg decades ago. Though it is a potential candidate for targeting against tumors, little is known about the mechanisms controlling it. Interestingly, such change in energy metabolism has been observed in several tissues during aging. However, the molecular pathways linking cancer, aging and metabolic reprogramming remain poorly characterized. Remarkably, we have recently identified the SIRT6 histone deacetylase as a central regulator of glycolytic metabolism: cells lacking SIRT6 undergo a dramatic metabolic switch, increasing lactate production while reducing mitochondrial respiration (Mostoslavsky et al., Cell 2006; Zhong et al., Cell 2010). More recently, we have found that SIRT6 is a potent tumor suppressor that inhibits cancer metabolism (Sebastian et al, Cell 2012). Inactivation of SIRT6 in cells leads to their transformation without the activation of a major oncogenic pathway and, in a mouse model of colorectal cancer, lack of SIRT6 increases the number, size and aggressiveness of tumors. Importantly, all these phenotypes are reversed by genetically or chemically inhibiting glycolysis, highlighting the driving role of glucose metabolism reprogramming in tumorigenesis. In this context, overexpression of SIRT6 in mice extends lifespan, a phenotype that is likely due to its tumor suppressor activity. Based on these findings, we hypothesize that decreased expression of SIRT6 during aging could switch glucose metabolism in tissues, favoring glycolytic-dependent tumorigenesis and tumor growth. In this grant, we will specifically: 1- Study the role of SIRT6 in metabolic reprogramming during aging. 2- Determine the role of SIRT6 as a tumor suppressor in aging-associated cancers by regulating glucose metabolism. Modulation of SIRT6 activity could provide us in the future with a potential therapeutic approach to reduce cancer incidence in the age population.

描述（由申请人提供）：衰老与生理功能的下降和几种疾病的主要发病率有关。其中，患癌症的风险随着年龄的增长而急剧增加。事实上，它与心脏病一起，是老年人死亡的第一个原因。除了随着年龄的增长逐渐积累突变之外，对衰老期间癌症发病率增加的分子机制知之甚少。癌细胞的一个突出特征是它们增加的葡萄糖摄取和对有氧糖酵解代谢的依赖，这是奥托瓦尔堡几十年前描述的现象。尽管它是一种潜在的靶向治疗肿瘤的候选药物，但对其控制机制知之甚少。有趣的是，在衰老过程中，在几种组织中观察到了这种能量代谢的变化。然而，连接癌症，衰老和代谢重编程的分子途径仍然缺乏特征。值得注意的是，我们最近已经鉴定了SIRT 6组蛋白脱乙酰酶作为糖酵解代谢的中心调节剂：缺乏SIRT 6的细胞经历显著的代谢转换，增加乳酸盐产生，同时减少线粒体呼吸（Mostoslavsky等人，Cell 2006; Zhong等人，Cell 2010）。最近，我们发现SIRT 6是抑制癌症代谢的有效肿瘤抑制因子（塞巴斯蒂安等人，Cell 2012）。细胞中SIRT 6的失活导致它们的转化，而不激活主要致癌途径，并且在结肠直肠癌的小鼠模型中，SIRT 6的缺乏增加了肿瘤的数量、大小和侵袭性。重要的是，所有这些表型都可以通过遗传或化学抑制糖酵解来逆转，突出了葡萄糖代谢重编程在肿瘤发生中的驱动作用。在这种情况下，小鼠中SIRT 6的过表达延长了寿命，这可能是由于其肿瘤抑制活性的表型。基于这些发现，我们假设衰老过程中SIRT 6表达的降低可以改变组织中的葡萄糖代谢，有利于糖酵解依赖性肿瘤发生和肿瘤生长。在这项资助中，我们将具体：1-研究SIRT 6在衰老过程中代谢重编程中的作用。2-确定SIRT 6作为肿瘤抑制因子通过调节葡萄糖代谢在衰老相关癌症中的作用。SIRT 6活性的调节可以在未来为我们提供一种潜在的治疗方法，以降低老年人群的癌症发病率。