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: 8318739
• 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/8318739
• 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

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.

过去，美国非霍奇金淋巴瘤（NHL）的发生率在过去已经大大增加 二十年。扩散的大B细胞淋巴瘤（DLBCL）是最常见的淋巴瘤 真正的国际研究占所有情况的三分之一。不幸的是，尽管如此 DLBCL的积极化学疗法仍然高死亡率说明了迫切需要创新的 方法。近年来，NHL的大多数进步来自特定疾病的发展 分子靶向剂。长期饮酒与增加的风险有关 各种器官的癌症。有趣的是，与实体瘤相反，存在流行病学 证据表明酒精会降低大多数非霍奇金淋巴瘤的风险。这 涉及这种矛盾和酒精引起的NHL发生率下降的机制 在很大程度上未知。其他人的先前工作表明乙醇降低了蛋白质 细胞中的合成，尽管该过程的基本调节机制尚未完全 理解。最近有证据表明慢性酒精摄入与 MTOR/P70 S6K信号通路的抑制，该途径在控制中起关键作用 重要的细胞过程，包括细胞存活和生长。因此，可能是酒精 - MTOR及其在人淋巴细胞中的效应子的依赖性抑制与降低有关 淋巴作用的发生率。该提议的中心假设是酒精直接抑制 MTOR和/或其效应子，导致抑制帽依赖性mRNA翻译和蛋白质 人淋巴细胞的合成；这种机制解释了抗淋巴瘤 酒精的特性。了解潜在的分子和生化机制 慢性饮酒抑制淋巴瘤的发育可能对发展很重要 预防和治疗淋巴瘤的新型策略。为此，我们将追求 一些调查线：1）直接在人淋巴细胞中抑制MTOR活性或 间接？ MTOR对上游MTOR调节剂（例如Pi 3'激酶和）有什么影响 Akt激酶？ 2）酒精会抑制P70 S6K活性及其下游效应子S6核糖体 蛋白质和真核引发因子4b？ 3）酒精对磷酸化的影响是什么 转化阻遏物4E-BP1和4E-BP1-EIF4E复合物的形成？什么是 酒精对正常人淋巴细胞和恶性淋巴瘤中帽依赖性翻译的影响 细胞？具体目的是：特定目标1：确定酒精是否表现出抑制作用 关于淋巴细胞和恶性淋巴瘤细胞中MTOR途径的激活，并鉴定 它表现出这种影响的机制。特定目的2：检查酒精对 MTOR途径的下游效应子的激活和功能，包括S6核糖体 蛋白质，EIF4B和4E-BP1。特定目的3：检查慢性乙醇暴露的能力 淋巴瘤异种移植物及其衰减p53 +/-淋巴瘤发展的能力 鼠标模型。总之，这些研究应有助于我们了解酒精的机制 抑制恶性淋巴瘤，可能构成开发创新方法的基础 阻断淋巴瘤的生长，包括未来的选择性和特定药理的设计 针对类似途径的代理。