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Mechanism of Chronic Alcohol Consumption-induced Cancer-Associated Cachexia

慢性饮酒诱发癌症相关恶病质的机制

基本信息

批准号：
9094210
负责人：
Hui Zhang
金额：
$ 45.3万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9094210
关键词：
Accounting Adipocytes Adipose tissue Advanced Malignant Neoplasm Affect Alcohol consumption Alcohols Autopsy Blood Body Weight Body Weight decreased Cancer Model Cancer Patient Catecholamines Cause of Death Cessation of life Data Development Epidemiology F-Box Proteins FOXO3A gene GDF8 gene Glycoproteins Goals Immune system Incidence Inflammatory Interleukin-6 Knowledge Life Lipase Lipolysis Malignant Neoplasms Malignant neoplasm of lung Modeling Molecular Mus Muscle Proteins Muscular Atrophy Pathway interactions Patients Process Production Protein Biosynthesis Proteins Quality of life Research Signal Pathway Skeletal Muscle Skeletal Muscle Neoplasm Syndrome TNF gene Testing Therapeutic Translating Ubiquitin United States Zinc activin A cancer cachexia cancer therapy cancer type chronic alcohol ingestion cytokine drinking water experience improved melanoma multicatalytic endopeptidase complex neoplastic cell prevent problem drinker protein degradation public health relevance skeletal muscle wasting statistics sterol esterase tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Cancer is the second leading cause of death in the United States. Around 80% of advanced cancer patients experience cancer-associated cachexia (CAC), a syndrome that is characterized by progressive loss of body weight and accounts for 25-30% of all cancer deaths. Alcohol consumption increases the incidence of multiple types of cancer. In the United States 3.5% of all cancer deaths (19,500) are alcohol-related. Each alcohol- related cancer death accounts for 17-19 years of potential life lost. Epidemiological data convincingly indicates that alcohol consumption not only increases the incidence of cancer, but also decreases the survival of cancer patients, especially these who have the types of cancer that induce CAC. However, it is not known whether alcohol consumption induces or enhances CAC, and whether the decreased survival is related to CAC. Lack of this knowledge hampers the development of effective therapeutic approaches for the treatment of cancer and the improvement of quality of life in alcoholics with cancer. Using a mouse B16BL6 melanoma model, we found that chronic alcohol consumption significantly enhances the loss of body weight, especially the loss of adipose tissue and skeletal muscle. In addition, alcohol consumption significantly up-regulates the expression of zinc- α2-glycoprotein (ZAG) and muscle atrophy F box protein (MAFbx), two signature proteins involved in CAC in tumor-bearing mice. These data clearly indicate that alcohol consumption enhances CAC. The objective of this project is to study the molecular mechanism of how chronic alcohol consumption enhances CAC. The central hypothesis is that the crosstalk between alcohol and the tumor: 1) enhances the catecholamine/β- adrenoreceptor signaling pathway to up-regulate the expression of ZAG, which in turn enhances the activity of hormone sensitive lipase and adipose triglyceride lipase to accelerate lipolysis in adipocytes; 2) increases inflammatory cytokines, TNF-α and IL-6, through activation of the immune system, and enhances tumor cell production of myostatin and activin A, which in turn increase the production of MAFbx and enhance the ubiquitin-proteasome pathway to degrade skeletal muscle proteins. To test these hypotheses and accomplish the objective we will pursue the following specific aims: 1) Determine the molecular mechanism of how alcohol enhances ZAG expression and further accelerates lipolysis in the adipocytes from melanoma-bearing mice; 2) Determine the mechanism underlying how alcohol activates MAFbx signaling pathway to enhance protein degradation in skeletal muscle of tumor-bearing mice; 3) Determine if the blockade of the ZAG and MAFbx signaling pathway can prevent the loss of adipose tissue and skeletal muscle, and improve the survival of alcohol-consuming and melanoma-bearing mice. The completion of the proposed research in this application will not only elucidate the molecular mechanism of how alcohol consumption activates different signaling pathways to enhances CAC, but also will provide promising targets for the development of effective therapeutic approaches to improve the quality of life and the survival of alcoholics with cancer.

描述（由申请人提供）：癌症是美国第二大死因。大约 80% 的晚期癌症患者患有癌症相关恶病质 (CAC)，这是一种以体重进行性下降为特征的综合征，占所有癌症死亡的 25-30%。饮酒会增加多种癌症的发病率。在美国，所有癌症死亡 (19,500 例) 的 3.5% 与酒精有关。每一起与酒精相关的癌症死亡都会导致 17-19 年的潜在寿命损失。流行病学数据令人信服地表明，饮酒不仅会增加癌症的发病率，还会降低癌症患者的生存率，尤其是那些患有诱发 CAC 的癌症类型的患者。然而，目前尚不清楚饮酒是否会诱发或增强 CAC，以及生存率下降是否与 CAC 有关。缺乏这方面的知识阻碍了治疗癌症的有效治疗方法的开发以及患有癌症的酗酒者生活质量的改善。使用小鼠 B16BL6 黑色素瘤模型，我们发现长期饮酒会显着加剧体重减轻，尤其是脂肪组织和骨骼肌的损失。此外，饮酒显着上调锌-α2-糖蛋白（ZAG）和肌肉萎缩F盒蛋白（MAFbx）的表达，这两种标志蛋白参与荷瘤小鼠的CAC。这些数据清楚地表明，饮酒可以增强 CAC。该项目的目的是研究长期饮酒如何增强 CAC 的分子机制。中心假设是酒精与肿瘤之间的串扰：1）增强儿茶酚胺/β-肾上腺素受体信号通路，上调ZAG的表达，进而增强激素敏感性脂肪酶和脂肪甘油三酯脂肪酶的活性，加速脂肪细胞的脂肪分解； 2）通过激活免疫系统，增加炎症细胞因子TNF-α和IL-6，并增强肿瘤细胞产生肌生长抑制素和激活素A，进而增加MAFbx的产生并增强泛素-蛋白酶体途径降解骨骼肌蛋白。为了检验这些假设并实现目标，我们将追求以下具体目标：1）确定酒精如何增强 ZAG 表达并进一步加速黑色素瘤小鼠脂肪细胞脂肪分解的分子机制； 2）确定酒精激活MAFbx信号通路以增强荷瘤小鼠骨骼肌蛋白质降解的机制； 3)确定阻断ZAG和MAFbx信号通路是否可以防止脂肪组织和骨骼肌的损失，并提高饮酒和患有黑色素瘤的小鼠的存活率。本申请中拟议研究的完成不仅将阐明饮酒如何激活不同信号通路以增强 CAC 的分子机制，而且还将为开发有效的治疗方法以改善生活质量和患有癌症的酗酒者的生存提供有希望的目标。