Alcohol Consumption and Risk of NHL: Role of MTOR Dysfunction

饮酒和 NHL 风险：MTOR 功能障碍的作用

• 批准号: 7925760
• 负责人: Ronald B Gartenhaus
• 金额: $ 35.27万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-05 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925760
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Attenuated; Biochemical; Biological; Cell Survival; Cell physiology; Cells; Chronic; Complex; Development; Diagnosis; Disease; Elderly; Epidemiologic Studies; Epidemiology; Ethanol; Eukaryotic Initiation Factors; Exhibits; Functional disorder; Future; Genetic Translation; Growth; Human; Incidence; International; Investigation; Liver diseases; Lymphocyte; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant lymphoid neoplasm; Molecular; Molecular Target; Non-Hodgkin' s Lymphoma; Organ; Pancreas; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Prevention; Process; Property; Protein Biosynthesis; Ribosomal Protein S6; Risk; Role; ST5 gene; Signal Pathway; Solid Neoplasm; TP53 gene; Toxic effect; Translations; Work; Xenograft procedure; alcohol effect; alcohol exposure; base; cancer risk; chemotherapy; chronic alcohol ingestion; design; eIF-4B; human FRAP1 protein; improved; innovation; large cell Diffuse non-Hodgkin' s lymphoma; mTOR Signaling Pathway; mTOR inhibition; mortality; mouse model; novel strategies; public health relevance

DESCRIPTION (provided by applicant): The incidence of Non-Hodgkin's lymphoma (NHL) in the USA has dramatically increased over the past two decades. Diffuse large B-cell lymphoma (DLBCL) is the most frequently diagnosed lymphoma in the REAL international study accounting for approximately a third of all cases. Unfortunately, despite aggressive chemotherapy for DLBCL the still high fatality rate illustrates the urgent need for innovative approaches. Most advances in NHL in recent years have come from development of disease-specific molecular targeted agents. Chronic alcohol consumption is associated with an increased risk for cancers of various organs. Interestingly, in contrast to solid tumors, there has been epidemiologic evidence indicating that alcohol decreases the risk for most types of non-Hodgkin's lymphoma. The mechanisms accounting for such paradoxical and alcohol-induced decrease in the incidence of NHL remain largely unknown. Previous work from others has shown that ethanol decreases protein synthesis in cells, although the underlying regulatory mechanisms of this process are not fully understood. There is recent evidence suggesting that chronic alcohol intake is associated with suppression of the mTOR/p70 S6K signaling pathway, a pathway that plays key roles in the control of important cellular processes, including cell survival and growth. It is therefore possible that alcohol-dependent inhibition of mTOR and its effectors in human lymphocytes is associated with decreased incidence of lymphomagenesis. The central hypothesis of this proposal is that alcohol directly inhibits mTOR and/or its effectors, resulting in suppression of cap-dependent mRNA translation and protein synthesis in human lymphocytes; and that such a mechanism accounts for the anti-lymphoma properties of alcohol. Understanding the underlying molecular and biochemical mechanisms by which chronic alcohol consumption suppresses lymphoma development may be important for developing novel strategies for the prevention and treatment of lymphoma. Towards this end we will pursue several lines of investigation: 1) Does alcohol suppress mTOR activity in human lymphocytes directly or indirectly? What are the effects of mTOR on upstream mTOR regulators such as the PI 3' kinase and the akt kinase? 2) Does alcohol inhibit p70 S6K activity and its downstream effectors S6 ribosomal protein and eukaryotic initiation factor 4B? 3) What are the effects of alcohol on the phosphorylation of the translational repressor 4E-BP1 and the formation of 4E-BP1-eIF4E complexes? What are the effects of alcohol on cap-dependent translation in normal human lymphocytes and malignant lymphoma cells? The specific aims are: Specific Aim 1: To determine whether alcohol exhibits suppressive effects on the activation of the mTOR pathway in lymphocytes and malignant lymphoma cells and to identify the mechanisms by which it exhibits such effects. Specific Aim 2: To examine the effects of alcohol on the activation and function of downstream effectors of the mTOR pathway, including S6 ribosomal protein, eIF4B and 4E-BP1. Specific Aim 3: To examine the ability of chronic ethanol exposure on lymphoma xenografts as well as its capacity to attenuate the development of lymphomas in a p53 mouse model. Altogether, these studies should help us understand the mechanisms by which alcohol inhibits malignant lymphomas and may form the basis for the development of innovative approaches to block lymphoma growth, including the future design of more selective and specific pharmacological agents that target similar pathways. PUBLIC HEALTH RELEVANCE: The incidence of Non-Hodgkin's lymphoma (NHL) in the USA has dramatically increased over the past two decades. Unfortunately, despite aggressive chemotherapy mortality is greater than 50% and is associated with significant toxicity especially in the elderly. The still high fatality rate illustrates the limitations of the existing therapies and the urgent need for innovative approaches. Most advances in NHL in recent years have come from development of disease-specific molecular targeted agents. A number of epidemiologic studies to date support the increasingly accepted view that current alcohol consumers have decreased risk of most types of non-Hodgkin's lymphoma. The underlying biological mechanism(s) for this negative association is unknown at present. EtOH decreases protein synthesis, and this effect is associated with changes in the phosphorylation status of several key components of the translational machinery. Chronic alcohol intake is associated with disruption of the mTOR-signaling pathway and recent finding with major relevance to this proposal, is that activation of the mTOR signaling pathway has recently been demonstrated in NHL providing strong rationale for the development of mTOR targeted therapy in lymphoid malignancies. Therefore, improved understanding of the underlying molecular mechanism(s) associated with the ability of EtOH to suppress mTOR activity may form the basis for the development of innovative approaches to block lymphoma growth.

描述（由申请人提供）：在过去二十年中，美国非霍奇金淋巴瘤（NHL）的发病率急剧增加。弥漫性大B细胞淋巴瘤（DLBCL）是真实的国际研究中最常诊断的淋巴瘤，约占所有病例的三分之一。不幸的是，尽管对DLBCL进行了积极的化疗，但仍然有很高的病死率，这说明迫切需要创新的方法。近年来NHL的最大进展来自疾病特异性分子靶向药物的开发。长期饮酒与各种器官癌症的风险增加有关。有趣的是，与实体瘤相反，有流行病学证据表明酒精降低了大多数类型非霍奇金淋巴瘤的风险。解释这种矛盾和酒精诱导的NHL发病率下降的机制在很大程度上仍然未知。其他人以前的工作表明，乙醇会降低细胞中的蛋白质合成，尽管这一过程的潜在调控机制尚未完全了解。最近有证据表明，长期酒精摄入与mTOR/p70 S6 K信号通路的抑制有关，该通路在控制重要细胞过程（包括细胞存活和生长）中起关键作用。因此，在人淋巴细胞中mTOR及其效应物的酒精依赖性抑制可能与淋巴瘤发生率降低相关。该提议的中心假设是酒精直接抑制mTOR和/或其效应物，导致人类淋巴细胞中帽依赖性mRNA翻译和蛋白质合成的抑制;并且这种机制解释了酒精的抗淋巴瘤特性。了解慢性饮酒抑制淋巴瘤发展的潜在分子和生化机制可能对开发预防和治疗淋巴瘤的新策略很重要。为此，我们将进行几条研究路线：1）酒精是否直接或间接抑制人类淋巴细胞中的mTOR活性？mTOR对上游mTOR调节因子如PI 3'激酶和akt激酶有什么影响？2)酒精是否抑制p70 S6 K活性及其下游效应子S6核糖体蛋白和真核起始因子4 B？3)酒精对翻译抑制因子4 E-BP 1的磷酸化和4 E-BP 1-eIF 4 E复合物的形成有什么影响？酒精对正常人淋巴细胞和恶性淋巴瘤细胞中帽依赖性翻译的影响是什么？具体目标是：具体目标1：确定酒精是否对淋巴细胞和恶性淋巴瘤细胞中mTOR通路的激活具有抑制作用，并确定其发挥这种作用的机制。具体目标二：检测酒精对mTOR通路下游效应物（包括S6核糖体蛋白、eIF 4 B和4 E-BP 1）的激活和功能的影响。具体目标3：在p53小鼠模型中检查淋巴瘤异种移植物长期乙醇暴露的能力及其减弱淋巴瘤发展的能力。总而言之，这些研究应该帮助我们了解酒精抑制恶性淋巴瘤的机制，并可能为开发阻断淋巴瘤生长的创新方法奠定基础，包括未来设计针对类似途径的更具选择性和特异性的药理学药物。 公共卫生相关性：在过去的二十年里，美国非霍奇金淋巴瘤（NHL）的发病率急剧增加。不幸的是，尽管积极的化疗死亡率大于50%，并与显着的毒性，特别是在老年人。仍然很高的死亡率说明了现有疗法的局限性和对创新方法的迫切需要。近年来NHL的最大进展来自疾病特异性分子靶向药物的开发。迄今为止，许多流行病学研究支持越来越被接受的观点，即目前的酒精消费者降低了大多数类型的非霍奇金淋巴瘤的风险。目前尚不清楚这种负相关的潜在生物学机制。乙醇降低蛋白质合成，这种作用与翻译机制的几个关键组分的磷酸化状态的变化有关。长期酒精摄入与mTOR信号传导通路的破坏相关，与该提议主要相关的最新发现是，最近在NHL中证实了mTOR信号传导通路的激活，这为在淋巴恶性肿瘤中开发mTOR靶向治疗提供了强有力的依据。因此，对与EtOH抑制mTOR活性的能力相关的潜在分子机制的更好理解可能构成开发阻断淋巴瘤生长的创新方法的基础。