Alcohol Consumption and Risk of NHL: Role of MTOR Dysfunction

非霍奇金淋巴瘤（NHL）在美国的发病率在过去急剧上升 二十年弥漫性大B细胞淋巴瘤（DLBCL）是最常见的淋巴瘤， 真实的国际研究约占所有病例的三分之一。不幸的是，尽管 DLBCL的侵袭性化疗仍然有很高的病死率，这说明迫切需要创新的治疗方法。 方法。近年来，NHL的大多数进展来自疾病特异性免疫球蛋白的发展。 分子靶向药物长期饮酒与以下风险增加有关： 各种器官的癌症。有趣的是，与实体瘤相比， 有证据表明，酒精可以降低大多数类型的非霍奇金淋巴瘤的风险。的 解释这种矛盾的机制和酒精诱导的NHL发病率下降 仍然在很大程度上未知。其他人先前的研究表明，乙醇会降低蛋白质含量， 在细胞中的合成，虽然这一过程的基本调控机制并不完全 明白最近有证据表明，长期饮酒与 抑制mTOR/p70 S6 K信号通路，该通路在控制 重要的细胞过程，包括细胞存活和生长。因此，酒精有可能- 人淋巴细胞中mTOR及其效应物的依赖性抑制与 淋巴瘤发生率。这个提议的中心假设是酒精直接抑制 mTOR和/或其效应物，导致帽依赖性mRNA翻译和蛋白质的抑制 在人类淋巴细胞的合成;这样的机制占抗淋巴瘤 酒精的特性。了解潜在的分子和生化机制， 长期饮酒抑制淋巴瘤的发展可能是重要的发展 预防和治疗淋巴瘤的新策略。为此，我们将继续 几条研究路线：1）酒精是否直接抑制人类淋巴细胞中的mTOR活性， 间接？mTOR对上游mTOR调节因子如PI 3'激酶和 Akt激酶2)酒精是否抑制p70 S6 K活性及其下游效应子S6核糖体 真核生物起始因子4 B？3)酒精对磷酸化的影响是什么？ 翻译抑制因子4 E-BP 1和4 E-BP 1-eIF 4 E复合物的形成？有哪些 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 细胞？具体目标1：确定酒精是否具有抑制作用 对淋巴细胞和恶性淋巴瘤细胞中mTOR通路的活化的影响，并鉴定 它表现出这种效果的机制。具体目标2：研究酒精对 mTOR通路下游效应子的激活和功能，包括S6核糖体 蛋白，eIF 4 B和4 E-BP 1。具体目标3：检查慢性乙醇暴露对 淋巴瘤异种移植物以及其在p53 +/- 小鼠模型总之，这些研究应该有助于我们了解酒精 抑制恶性淋巴瘤，并可能成为开发创新方法的基础， 阻断淋巴瘤生长，包括未来设计更具选择性和特异性的药理学 针对类似途径的药物。

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.