Alcohol Consumption and Risk of NHL: Role of MTOR Dysfunction

描述（由申请人提供）：在过去的二十年中，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REAL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，但死亡率仍然很高，这表明迫切需要创新的方法。近年来，NHL的大多数进展都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。这种矛盾的和酒精引起的NHL发病率下降的机制在很大程度上仍然未知。其他人先前的研究表明，乙醇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，慢性酒精摄入与mTOR/p70 S6K信号通路的抑制有关，mTOR/p70 S6K信号通路在控制包括细胞存活和生长在内的重要细胞过程中起关键作用。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发生率的降低有关。该建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；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，可能对制定预防和治疗淋巴瘤的新策略具有重要意义。为此，我们将进行以下几方面的研究：1)酒精是否直接或间接地抑制人类淋巴细胞中的mTOR活性？mTOR对上游mTOR调控因子如pi3 '激酶和akt激酶有什么影响？2)酒精是否抑制p70 S6K活性及其下游效应物S6核糖体蛋白和真核起始因子4B？3)酒精对翻译抑制因子4E-BP1的磷酸化和4E-BP1- eif4e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帽依赖性翻译的影响是什么？具体目的如下：具体目的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，并确定其表现出这种作用的机制。具体目的2：研究酒精对mTOR途径下游效应物的激活和功能的影响，包括S6核糖体蛋白、eIF4B和4E-BP1。特异性目的3：在p53小鼠模型中，研究慢性乙醇暴露对淋巴瘤异种移植的能力及其减弱淋巴瘤发展的能力。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。

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.