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: 8515885
• 负责人: Ronald B Gartenhaus
• 金额: $ 31.53万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515885
• 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) 的发病率急剧上升 二十年。弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常诊断的淋巴瘤 真实的国际研究约占所有案例的三分之一。不幸的是，尽管 DLBCL 的积极化疗死亡率仍然很高，说明迫切需要创新药物 接近。近年来 NHL 的大部分进展都来自于疾病特异性药物的开发 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，流行病学 有证据表明酒精可降低大多数类型非霍奇金淋巴瘤的风险。这 酒精导致 NHL 发病率下降的机制 仍然很大程度上不为人知。其他人之前的研究表明乙醇会降低蛋白质含量 细胞内的合成，尽管这一过程的潜在调节机制尚不完全清楚 明白了。最近的证据表明，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，包括细胞存活和生长。因此，酒精有可能—— 人淋巴细胞中 mTOR 及其效应子的依赖性抑制与降低 淋巴瘤发生的发生率。该提案的中心假设是酒精直接抑制 mTOR 和/或其效应子，导致帽依赖性 mRNA 翻译和蛋白质的抑制 人类淋巴细胞的合成；并且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 长期饮酒抑制淋巴瘤的发展可能对发展很重要 预防和治疗淋巴瘤的新策略。为此我们将追求 几方面的研究：1) 酒精是否直接抑制人类淋巴细胞中的 mTOR 活性，或者 间接？ mTOR 对上游 mTOR 调节因子（例如 PI 3' 激酶和 PI 3' 激酶）有何影响？ akt 激酶？ 2）酒精是否会抑制p70 S6K活性及其下游效应子S6核糖体 蛋白质和真核起始因子4B？ 3）酒精对磷酸化有什么影响？ 翻译抑制子 4E-BP1 和 4E-BP1-eIF4E 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中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，并鉴定 它表现出这种效果的机制。具体目标 2：检查酒精对 mTOR 通路下游效应子的激活和功能，包括 S6 核糖体 蛋白质、eIF4B 和 4E-BP1。具体目标 3：检验长期接触乙醇对健康的影响 淋巴瘤异种移植物及其减弱 p53 +/- 淋巴瘤发展的能力 鼠标模型。总而言之，这些研究应该有助于我们了解酒精的机制 抑制恶性淋巴瘤，并可能成为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理学药物 针对类似途径的药物。

项目成果

Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders.

• DOI: 10.1038/onc.2015.364
• 发表时间: 2016-06-09
• 期刊: Oncogene
• 影响因子: 8
• 作者: Dai B;Chen AY;Corkum CP;Peroutka RJ;Landon A;Houng S;Muniandy PA;Zhang Y;Lehrmann E;Mazan-Mamczarz K;Steinhardt J;Shlyak M;Chen QC;Becker KG;Livak F;Michalak TI;Talwani R;Gartenhaus RB
• 通讯作者: Gartenhaus RB