Mechanism of Chronic Alcohol Consumption-induced Cancer-Associated Cachexia

 描述(申请人提供)：癌症是美国第二大死因。大约80%的晚期癌症患者经历癌症相关性恶病质(CAC)，这是一种以体重逐渐减轻为特征的综合征，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，3.5%的癌症死亡(19,500人)与酒精有关。每一例与酒精相关的癌症死亡占潜在寿命损失的17-19年。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存活率，特别是那些患有诱发CAC的癌症类型的患者。然而，目前尚不清楚饮酒是诱导还是增强了CAC，以及生存率的下降是否与CAC有关。缺乏这方面的知识阻碍了癌症治疗的有效治疗方法的发展和患有癌症的酗酒者生活质量的提高。利用小鼠B16BL6黑色素瘤模型，我们发现长期饮酒显著增加了体重的减轻，特别是脂肪组织和骨骼肌的丢失。此外，饮酒显著上调锌-α2-糖蛋白(ZAG)和肌肉萎缩F盒蛋白(MAFbx)的表达，这两种蛋白与荷瘤小鼠的CAC有关。这些数据清楚地表明，饮酒会增强CAC。本项目的目的是研究长期饮酒促进CAC的分子机制。中心假说是酒精与肿瘤之间的串扰：1)加强儿茶酚胺/β-肾上腺素受体信号通路，上调ZAG的表达，进而增强激素敏感脂肪酶和脂肪甘油三酯脂肪酶的活性，以加速脂肪细胞的脂肪分解；2)通过激活免疫系统，增加炎性细胞因子，肿瘤坏死因子-α和IL-6，并增强肿瘤细胞产生的肌肉抑制素和激活素A，进而增加MAFbx的产生，并增强泛素-蛋白酶体途径以降解骨骼肌蛋白质。为了验证这些假设并实现这一目标，我们将追求以下具体目标：1)确定酒精如何促进荷瘤小鼠脂肪细胞ZAG表达并进一步加速脂解的分子机制；2)确定酒精如何激活MAFbx信号通路从而促进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丢失，并改善饮酒和黑色素瘤小鼠的生存。这项应用研究的完成不仅将阐明酒精消费如何激活不同信号通路以增强CAC的分子机制，而且将为开发有效的治疗方法以提高癌症患者的生活质量和生存提供有希望的靶点。

 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.