Alcohol Consumption and Risk of NHL: Role of MTOR Dysfunction

描述(申请人提供)：非霍奇金淋巴瘤(NHL)在美国的发病率在过去20年里急剧增加。弥漫性大B细胞淋巴瘤(DLBCL)是真正的国际研究中最常见的诊断淋巴瘤，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，但死亡率仍然很高，这表明迫切需要创新的方法。近年来，非霍奇金淋巴瘤的大部分进展来自于疾病特异性分子靶向药物的开发。长期饮酒会增加患各种器官癌症的风险。有趣的是，与实体肿瘤相比，有流行病学证据表明酒精降低了大多数类型的非霍奇金淋巴瘤的风险。酒精引起的非霍奇金淋巴瘤发病率下降的机制目前仍不清楚。其他人之前的工作已经表明，乙醇减少了细胞中蛋白质的合成，尽管这一过程的潜在调控机制还不完全清楚。最近有证据表明，长期饮酒与mTOR/p70 S6K信号通路的抑制有关，该通路在控制重要的细胞过程，包括细胞的生存和生长方面发挥着关键作用。因此，酒精依赖抑制人淋巴细胞中mTOR及其效应物可能与降低淋巴肿大的发生率有关。这一建议的中心假设是酒精直接抑制mTOR和/或其效应物，导致抑制人淋巴细胞帽子依赖的mRNA翻译和蛋白质合成；这种机制解释了酒精抗淋巴瘤的特性。了解长期饮酒抑制淋巴瘤发展的潜在分子和生化机制对于开发预防和治疗淋巴瘤的新策略可能是重要的。为此，我们将进行以下几个方面的研究：1)酒精是否直接或间接地抑制人淋巴细胞中的mTOR活性？MTOR对pI3‘和AKT等上游mTOR调节因子有何影响？2)酒精是否抑制p70 S6K活性及其下游效应因子S6核糖体蛋白和真核细胞起始因子4B？3)酒精对翻译抑制物4E-BP1的磷酸化和4E-BP1-eIF4E复合体的形成有何影响？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：特定目标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，并确定其表现这种作用的机制。具体目的2：研究酒精对mTOR途径下游效应分子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小鼠模型中检测慢性酒精暴露对淋巴瘤异种移植瘤的能力以及其抑制淋巴瘤发展的能力。总之，这些研究应该有助于我们理解酒精抑制恶性淋巴瘤的机制，并可能形成开发阻止淋巴瘤生长的创新方法的基础，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：非霍奇金淋巴瘤(NHL)在美国的发病率在过去20年里急剧增加。不幸的是，尽管进行了积极的化疗，但死亡率仍高于50%，并与显著的毒性有关，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，非霍奇金淋巴瘤的大部分进展来自于疾病特异性分子靶向药物的开发。到目前为止，一些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。这种负面关联的潜在生物学机制(S)目前尚不清楚。乙醇减少了蛋白质的合成，这种影响与翻译机械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，最近的研究发现，最近在NHL中发现了mTOR信号通路的激活，这为发展mTOR靶向治疗淋巴系统恶性肿瘤提供了强有力的理论基础。因此，更好地理解乙醇抑制mTOR活性的潜在分子机制(S)可能成为开发阻断淋巴瘤生长的创新方法的基础。

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.