CRITICAL SULFHYDRYL SWITCHES, DIET, AND CANCER PREVENTION WORKSHOP Executive Summary OPENING REMARKS Welcome Peter Greenwald, Director, Division of Cancer Prevention John Milner, Nutritional Sciences Research Group, Division of Cancer Prevention Peter Greenwald, M.D., Ph.D., Director, Division of Cancer Prevention (DCP), National Cancer Institute (NCI), National Institutes of Health (NIH), welcomed participants and explained that NCI has been working to enhance the field of basic nutritional science and its relationship to cancer prevention. He noted there was evidence from the fields of epidemiology and behavioral science that diet can have an impact on cancer risk but that the literature is full of inconsistencies. A better understanding of the molecular basis for the association between diet and cancer risk be developed will help resolve these uncertainties. The food supply is undergoing fundamental changes as modern technologies that were developed for medical research are applied to food and agriculture, and it is imperative that the changes benefit the public. It is particularly important to have scientists from different fields come together to share ideas to increase our knowledge of nutritional science. John Milner, Ph.D., Chief, Nutritional Sciences Research Group (NSRG), DCP, NCI, NIH, welcomed participants and thanked Dr. Jeffery for her efforts in organizing the workshop. He presented information on government sponsored funding—approximately $860 million—of nutrition-related research throughout the Federal Government. The NCI is spending approximately $204 million of the total, which is a considerable commitment designed to increase our understanding of nutrition and cancer risk. This effort is focused on understanding the reasons for so much variability in response to diet among populations, and how this variability translates into variable risks. This means looking at mechanisms of action of specific nutrients and diets, and focusing on nutrigenetics and nutrigenomics as potential factors for addressing this variability. There is another critical step following nutrigenetics and nutrigenomics, that of post-translational modification of proteins, that may help with our understanding of this complex issue. This workshop’s focus on thiol modification of proteins may help us to understand what changes occur that account for some of the variation in response to bioactive components. The NCI focuses on three steps in the research/translation process: discovery, development, and delivery. He noted that nutritional sciences is to a large degree in the discovery mode and thus devoting considerable attention to possible mechanism(s) by which bioactive food components work. There need to be new analytical methods and approaches applied to the discovery of these mechanisms. There also is a need to understand molecular targets and use this information to determine what factors are important for the health of the individual. Knowledge about sites of action should allow for a personalized approach to nutrition that might best be described at "nutritional preemption." Describing the Challenge Elizabeth H. Jeffery, University of Illinois Elizabeth H. Jeffery, Ph.D., Professor, University of Illinois at Urbana, and a visiting scholar at NSRG, DCP, NCI, NIH, provided the perspective that in the past decade there has been growing interest in bioactive food components and diet as significant factors in the level of risk for cancer and other diseases. Dr. Jeffery recognized that participants in the workshop come from a variety of research backgrounds. In general, there are those that think about cancer biology and how thiols affect the biology in the cancer cell, and those who think about bioactive food components that are thiols or thiol-reactive compounds. The task of the workshop will be to bring these two fields of research together to gain a better understanding of the role of thiolation of proteins in effecting changes in cancer risk through diet. Many thiols may have effects at the genomic and epigenomic levels. However, this workshop will focus on the impact of post-translational modification of proteins and the role of thiols in affecting cellular signaling through thiol redox and thiolation, just as we know that protein phosphorylation produces post-translation changes in protein activities. It is important to know how this occurs with thiols. In the diet, there are thiol-containing nutrients and non-nutrients (e.g., cysteine and allyl sulfide) that may be interacting with the thiol system. Perturbation of protein thiolation could also be the mechanism for a large number of bioactive components that do not contain thiols but are thiol-reactive, such as sulforaphane from broccoli or selenium-containing compounds. Dr. Jeffery reviewed the agenda and listed the subjects to be covered in each session of the workshop: Session 1: Setting the Scene: Differentiating between thiol-active redox reactions and reactive oxygen species (ROS)/ oxidative damage; Session 2: Technologies that can be applied to this area; Session 3: Diet and thiol regulation; Session 4: Molecular mechanisms that may be involved in thiol regulation; See pages below for each session section. SUMMARY Thiol-reactive compounds, presently recognized as antioxidants appear to have a role in cellular physiology, protecting against carcinogenesis. Information is incomplete, but points toward thiol-rich foods being able to provide such protection. Quenching or reversing the action of radicals, such as reactive oxygen species, is not the full story behind the health benefits of the bioactive food components loosely described as "antioxidants." Sulfhydryl oxidation/reduction and/or thiolation causing redox modifications of cellular proteins regulate a wide number of cell pathways associated with proliferation, differentiation and apoptosis. There is not a constant, or even a single, redox equilibrium within cells-and redox changes with cell type and cellular health status, such as damaged or aging cells. It brings in activity of a cys/cySS couple both inside and outside the cell, as well as glutathione and thioredoxin couples. Cell culture is carried out at falsely high oxygen tensions that may confound the study of regulation by redox. Methods for studying thiols and thiolation need further development. Dysfunction of redox systems such as GSH/GSSG is an integral part of the manifestation of many diseases: redox changes due to disease state and/or aging could be an early biomarker used as a measure of health and wellness. Redox status can be altered by certain radicals and other chemicals, including sulfur amino acids and a number of bioactive food components thought of as antioxidants. This summary is from the NIH website: http://www3.cancer.gov/prevention/cssd/summary.html 4/05 NIH meeting, August, 2003 August, 2003 NIH Meeting NIH meeting, 8/03 NIH meeting, 8/03 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.