SESSION 3: DIET AND THIOL REGULATION OF THE CELL CYCLE Do Cancer Cells Have an Aberrant Thiol Status In Vivo That Responds to Diet? Garry R. Buettner, University of Iowa Does Dietary Cysteine Regulation of the Cell Cycle Provide Clues to Additional Dietary Influences? Dean P. Jones, Emory University How Do Dietary Alterations in Glutathione and Thioredoxin Levels Affect Cell Cycle? Arne Holmgren, Karolinska Institute Garry R. Buettner, Ph.D., Professor, Department of Radiation Oncology/Free Radical and Radiation Biology, University of Iowa, Iowa City, described the changes in thiol status as a cell progresses from a proliferating stem cell, through differentiation to end in apoptosis, and the finding that cancer cells differ from non-transformed cells in their redox status. Dean P. Jones, Ph.D., Professor, Department of Biochemistry, Emory University, Atlanta, Georgia also discussed redox regulation of the cell cycle, focusing on changes effected by dietary cysteine. Arne Holmgren, M.D., Professor, Medical Biochemistry and Biophysics/Medical Nobel Institute for Biochemistry, Karolinska Institute, Stockholm, Sweden, presented further information on cancer cell proliferation and cell cycle changes related to diet-directed alterations in intracellular GSH and thioredoxin. Studies on diet, antioxidants, and redox status reflect a relationship between sulfhydryl biochemistry and cancer, although they rarely address the topic directly. Results of these studies indicate that dietary antioxidant factors, including lycopene and other carotenoids and flavonoids have been implicated in mitigating the progression of prostate cancer. Whereas many "antioxidant anticarcinogens" like these are possibly best recognized for their effects on the induction of Phase II detoxification enzymes, they also cause elevation of tissue GSH levels, demonstrating the potential for an effect on sulfhydryl switches, as a mechanism for their influence on cancer risk. Normal cells are metabolically highly reduced during proliferation. As these cells progress from proliferation to differentiation, they pass to a more oxidized state. As differentiation is completed, these cells return to a more reduced state. However, cells that progress further to apoptosis do not undergo reduction, but become further oxidized. Research is needed to determine whether changes in redox are instrumental in directing the cell through these various stages. Experiments suggest that the redox of the proliferating cancer cell is shifted to a more oxidized state, one that in normal cells would be associated with the initiation of differentiation. That this switch to differentiation does not occur in the cancer cell is clear – but whether further manipulation of the redox status can trigger such a switch, or whether the switch(es) that normally respond to an oxidative change in a non-cancerous cell are missing in the cancer cell is unclear. Several classic dietary antioxidants, such as selenium and lipoic acid are known to increase antioxidant enzymes like glutathione peroxidase, but whether this is implicated in the anticarcinogenic actions of these antioxidants is unknown. Models are needed that allow the study of redox in an environment more closely reflecting oxygen tensions found in tissues. Such models can be used to define the pathways triggered by redox changes, providing an understanding of whether changes in redox occur as a result of passage through the cell cycle, or if redox, at least in part, directs passage through the cell cycle. Looking in more depth at the changes from reduced to oxidized as the cell passes from proliferation to differentiation and apoptosis, one sees that whereas this is true for glutathione, that the cys/cySS couple remains oxidized through out the cell cycle, and that thioredoxin, in nucleus but also in cytosol and the mitochondrion, tends to stay more reduced throughout the cell cycle. Thus not only may redox be compartmentalized within the cell, but depending upon the precise protein environment, differential oxidation of protein sulfhydryls would be expected to occur. Regulatory mechanisms could allow a series of proteins to be activated and then inactivated as the cell progressed from more reduced to more oxidized. For example, even under cellular conditions associated with apoptosis, thioredoxin remains reduced. Whether this is due to the protein environment or to subcellular compartmentalization of factors causing a redox change is unclear. What is clear is that the glutathione/glutaredoxin pathway for reduction of cellular components is quite separate from the thioredoxin pathway of reduction. Thus in a single cell at a given intracellular redox, a sulfhydryl switch could be reduced by thioredoxin and then oxidized by glutathione. Furthermore, cellular proliferation may be regulated by both intracellular and extracellular thiol status: It is known that thiol status regulates expression of both Fas death receptor and the Fas ligand, on the exterior surface of the cell membrane. Without protein cofactors, a mix of glutathione and cysteine couples will eventually reach redox equilibrium; although this is a slow process. This helps to understand that in the cell, one can have a relatively oxidized cysteine couple, a relatively reduced thioredoxin couple, and that the greatest range for variation and therefore for physiological effects is associated with glutathione. Entrance of cysteine into the cell might be sufficient to allow oxidation without the need for ROS initiation, so that by regulating cysteine influx, the cell might regulate passage from proliferation to differentiation. In studies designed to do just this, one finds that growth factors are completely able to over-ride any cysteine redox effects, reminiscent of the redundancy theory of alternative pathways. August, 2003 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.