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显著增加 二十年了。弥漫性大B细胞淋巴瘤(DLBCL)是 真正的国际研究约占所有病例的三分之一。不幸的是，尽管 DLBCL的积极化疗死亡率仍然很高，说明迫切需要创新 接近了。近年来，非霍奇金淋巴瘤的大多数进展来自于疾病特异性的发展。 分子靶向制剂。长期饮酒与患高血压的风险增加有关 各种器官的癌症。有趣的是，与实体肿瘤不同的是， 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。这个 解释这种矛盾和酒精诱导的NHL发病率下降的机制 在很大程度上仍然不为人知。其他人之前的研究表明，乙醇会减少蛋白质 在细胞中的合成，尽管这一过程的潜在调节机制并不完全 明白了。最近有证据表明，长期饮酒与 抑制mTOR/p70 S6K信号通路，该通路在控制 重要的细胞过程，包括细胞的生存和生长。因此，酒精有可能- 人淋巴细胞mTOR及其效应器的依赖抑制与减少相关 淋巴增生症的发生率。这一提议的中心假设是酒精直接抑制 MTOR和/或其效应物，导致抑制帽依赖的mRNA翻译和蛋白 人类淋巴细胞的合成；以及这种机制解释了抗淋巴瘤 酒精的性质。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对淋巴瘤的发生具有重要意义 预防和治疗淋巴瘤的新策略。为此，我们将致力于 有几条研究路线：1)酒精是直接还是直接抑制人淋巴细胞中mTOR活性 间接的？MTOR对上游mTOR调节因子如PI3‘激酶和 2)酒精能抑制p70 S6K活性及其下游效应因子S6核糖体吗？ 蛋白质和真核细胞起始因子4B？3)酒精对蛋白磷酸化有什么影响 翻译抑制因子4E-BP1和4E-BP1-eIF4E复合体的形成？什么是 酒精对正常人淋巴细胞和恶性淋巴瘤细胞帽子依赖性翻译的影响 细胞？具体目标是：具体目标1：确定酒精是否具有抑制作用 淋巴细胞和恶性淋巴瘤细胞中mTOR通路的激活及鉴定 它表现出这种效果的机制。具体目标2：研究酒精对人体健康的影响 包括S6核糖体在内的mTOR途径下游效应物的激活和功能 蛋白质、eIF4B和4E-BP1。具体目标3：检测慢性酒精暴露对小鼠的影响 淋巴瘤异种移植及其抑制P53+/-淋巴瘤发展的能力 老鼠模型。总之，这些研究应该有助于我们理解酒精 抑制恶性淋巴瘤，并可能形成开发创新方法的基础 阻止淋巴瘤生长，包括未来设计更具选择性和特异性的药物 以类似途径为目标的药物。

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.