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- ?2-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/?- 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-? 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.

Public Health Relevance

This project is to investigate how chronic alcohol consumption enhances cancer-associated cachexia (CAC), especially the accelerated loss of adipose tissue and skeletal muscle in cancer hosts. Finding the mechanism of chronic alcohol consumption enhancing CAC will provide promising targets for the development of effective therapeutic approaches to improve the quality of life and to increase the survival of cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15AA024284-01A1
Application #
9094210
Study Section
Special Emphasis Panel (ZRG1-MOSS-U (82)A)
Program Officer
Dunty, Jr, William
Project Start
2016-09-01
Project End
2019-03-31
Budget Start
2016-09-01
Budget End
2019-03-31
Support Year
1
Fiscal Year
2016
Total Cost
$453,000
Indirect Cost
$153,000
Name
Washington State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Wang, Bo; Zhang, Faya; Zhang, Hui et al. (2017) Alcohol intake aggravates adipose browning and muscle atrophy in cancer-associated cachexia. Oncotarget 8:100411-100420