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      Cancer, Oxidative Stress, and Metastasis.

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          Abstract

          Reactive oxygen species (ROS) are highly reactive molecules that arise from a number of cellular sources, including oxidative metabolism in mitochondria. At low levels they can be advantageous to cells, activating signaling pathways that promote proliferation or survival. At higher levels, ROS can damage or kill cells by oxidizing proteins, lipids, and nucleic acids. It was hypothesized that antioxidants might benefit high-risk patients by reducing the rate of ROS-induced mutations and delaying cancer initiation. However, dietary supplementation with antioxidants has generally proven ineffective or detrimental in clinical trials. High ROS levels limit cancer cell survival during certain windows of cancer initiation and progression. During these periods, dietary supplementation with antioxidants may promote cancer cell survival and cancer progression. This raises the possibility that rather than treating cancer patients with antioxidants, they should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance.

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          TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

          The p53 tumor-suppressor protein prevents cancer development through various mechanisms, including the induction of cell-cycle arrest, apoptosis, and the maintenance of genome stability. We have identified a p53-inducible gene named TIGAR (TP53-induced glycolysis and apoptosis regulator). TIGAR expression lowered fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels. These functions of TIGAR correlated with an ability to protect cells from ROS-associated apoptosis, and consequently, knockdown of endogenous TIGAR expression sensitized cells to p53-induced death. Expression of TIGAR may therefore modulate the apoptotic response to p53, allowing survival in the face of mild or transient stress signals that may be reversed or repaired. The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage.
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            The thioredoxin antioxidant system.

            The thioredoxin (Trx) system, which is composed of NADPH, thioredoxin reductase (TrxR), and thioredoxin, is a key antioxidant system in defense against oxidative stress through its disulfide reductase activity regulating protein dithiol/disulfide balance. The Trx system provides the electrons to thiol-dependent peroxidases (peroxiredoxins) to remove reactive oxygen and nitrogen species with a fast reaction rate. Trx antioxidant functions are also shown by involvement in DNA and protein repair by reducing ribonucleotide reductase, methionine sulfoxide reductases, and regulating the activity of many redox-sensitive transcription factors. Moreover, Trx systems play critical roles in the immune response, virus infection, and cell death via interaction with thioredoxin-interacting protein. In mammalian cells, the cytosolic and mitochondrial Trx systems, in which TrxRs are high molecular weight selenoenzymes, together with the glutathione-glutaredoxin (Grx) system (NADPH, glutathione reductase, GSH, and Grx) control the cellular redox environment. Recently mammalian thioredoxin and glutathione systems have been found to be able to provide the electrons crossly and to serve as a backup system for each other. In contrast, bacteria TrxRs are low molecular weight enzymes with a structure and reaction mechanism distinct from mammalian TrxR. Many bacterial species possess specific thiol-dependent antioxidant systems, and the significance of the Trx system in the defense against oxidative stress is different. Particularly, the absence of a GSH-Grx system in some pathogenic bacteria such as Helicobacter pylori, Mycobacterium tuberculosis, and Staphylococcus aureus makes the bacterial Trx system essential for survival under oxidative stress. This provides an opportunity to kill these bacteria by targeting the TrxR-Trx system. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.

              Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
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                Author and article information

                Journal
                Cold Spring Harb. Symp. Quant. Biol.
                Cold Spring Harbor symposia on quantitative biology
                Cold Spring Harbor Laboratory
                1943-4456
                0091-7451
                2016
                : 81
                Affiliations
                [1 ] Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
                [2 ] Department of Pediatrics, Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
                [3 ] Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
                Article
                sqb.2016.81.030791
                10.1101/sqb.2016.81.030791
                28082378
                5f403126-2027-4065-aea9-25937760a171
                History

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