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: 8127669
• 负责人: Ronald B Gartenhaus
• 金额: $ 33.9万
• 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/8127669
• 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; Signal Pathway; Solid Neoplasm; Toxic effect; Translations; Work; Xenograft procedure; alcohol effect; alcohol exposure; alcohol risk; base; cancer risk; cell growth; 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）：过去二十年来，美国非霍奇金淋巴瘤（NHL）的发病率急剧增加。 REAL 国际研究中，弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常诊断的淋巴瘤，约占所有病例的三分之一。不幸的是，尽管 DLBCL 采取了积极的化疗，但死亡率仍然很高，这表明迫切需要创新方法。近年来 NHL 的大部分进展都来自于疾病特异性分子靶向药物的开发。长期饮酒与多种器官癌症的风险增加有关。有趣的是，与实体瘤相比，有流行病学证据表明酒精可降低大多数类型非霍奇金淋巴瘤的风险。这种由酒精引起的自相矛盾的 NHL 发病率下降的机制在很大程度上仍不清楚。其他人之前的研究表明，乙醇会减少细胞中的蛋白质合成，尽管这一过程的潜在调节机制尚未完全了解。最近有证据表明，长期饮酒与 mTOR/p70 S6K 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）中发挥关键作用。因此，人类淋巴细胞中 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有关。该提案的中心假设是酒精直接抑制 mTOR 和/或其效应器，从而抑制人淋巴细胞中帽子依赖性 mRNA 翻译和蛋白质合成；并且这种机制解释了酒精的抗淋巴瘤特性。了解长期饮酒抑制淋巴瘤发展的潜在分子和生化机制可能对于制定预防和治疗淋巴瘤的新策略很重要。为此，我们将进行几方面的研究：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（例如 PI 3' 激酶和 akt 激酶）有何影响？ 2）酒精是否会抑制p70 S6K活性及其下游效应子S6核糖体蛋白和真核起始因子4B？ 3) 酒精对翻译抑制子4E-BP1的磷酸化和4E-BP1-eIF4E复合物的形成有何影响？酒精对正常人淋巴细胞和恶性淋巴瘤细胞的帽子依赖性翻译有何影响？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 通路的激活表现出抑制作用，并确定其表现出这种作用的机制。具体目标 2：检查酒精对 mTOR 通路下游效应子（包括 S6 核糖体蛋白、eIF4B 和 4E-BP1）的激活和功能的影响。具体目标 3：在 p53 小鼠模型中检查慢性乙醇暴露对淋巴瘤异种移植物的作用及其减弱淋巴瘤发展的能力。总而言之，这些研究应帮助我们了解酒精抑制恶性淋巴瘤的机制，并可能为开发阻止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物制剂。 公共卫生相关性：过去二十年来，美国非霍奇金淋巴瘤 (NHL) 的发病率急剧增加。不幸的是，尽管积极化疗，死亡率仍高于 50%，并且与显着的毒性相关，尤其是在老年人中。仍然很高的死亡率说明了现有疗法的局限性以及对创新方法的迫切需要。近年来 NHL 的大部分进展都来自于疾病特异性分子靶向药物的开发。迄今为止的许多流行病学研究支持了越来越被接受的观点，即当前的饮酒者患大多数类型非霍奇金淋巴瘤的风险降低了。目前尚不清楚这种负关联的潜在生物学机制。 EtOH 会降低蛋白质合成，这种效应与翻译机制的几个关键组件的磷酸化状态的变化有关。慢性酒精摄入与 mTOR 信号通路的破坏有关，与该提议主要相关的最新发现是，最近在 NHL 中证明了 mTOR 信号通路的激活，为淋巴恶性肿瘤中 mTOR 靶向治疗的开发提供了强有力的理由。因此，更好地了解与 EtOH 抑制 mTOR 活性的能力相关的潜在分子机制可能会成为开发阻止淋巴瘤生长的创新方法的基础。