Hindawi Publishing Corporation International Journal of Cell Biology Volume 2012, Article ID 486147, 8 pages doi:10.1155/2012/486147 Review Article The Yin and Yang of Nrf2-Regulated Selenoproteins in Carcinogenesis Regina Brigelius-Flohe´ , Mike M u¨ller, Doris Lippmann, and Anna Patricia Kipp Department Biochemistry of Micronutrients, German Institute of Human Nutrition, Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany Correspondence should be addressed to Regina Brigelius-Flohe´, ﬂohe@dife.de Received 1 February 2012; Accepted 20 February 2012 Academic Editor: Giuseppe Filomeni Copyright © 2012 Regina Brigelius-Flohe´ et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The NF-E2-related factor-2 (Nrf2) is a transcription factor which regulates the major cellular defense systems and thereby contributes to the prevention of many diseases including cancer. Selenium deﬁciency is associated with a higher cancer risk making also this essential trace element a promising candidate for cancer prevention. Two selenoproteins, thioredoxin reductase-1 (TrxR1) and glutathione peroxidase-2 (GPx2), are targets for Nrf2. Selenium deﬁciency activates Nrf2 as does a TrxR1 knockout making a synergism between both systems plausible. Although this might hold true for healthy cells, the interplay may turn into the opposite in cancer cells. The induction of the detoxifying and antioxidant enzymes by Nrf2 will make cancer cells chemoresistant and will protect them against oxidative damage. The essential role of TrxR1 in maintaining proliferation makes its upregulation in cancer cells detrimental. The anti-inﬂammatory potential of GPx2 will help to inhibit cancer initiation and inﬂammation- triggered promotion, but its growth supporting potential will also support tumor growth. This paper considers beneﬁcial and adverse consequences of the activation of Nrf2 and the selenoproteins which appear to depend on the cancer stage. 1. Introduction An adequate-to-high selenium supply and activation of Nrf2 by dietary compounds are considered to substantially help to prevent cancer development. Selenium exerts its eﬀects mainly as part of selenoproteins with redox functions, and Nrf2 upregulates enzymes of the adaptive response. Thus, both systems are involved in the equipment of cells with a network of enzymes which are supposed to counteract the transformation of healthy into cancer cells by oxida- tive damage. However, not all attempts to prevent cancer by respective dietary supplementation/intervention ended up with a beneﬁcial outcome; even harmful eﬀects were observed. The so-called Linxian trial was among the ﬁrst large ran- domized, double-blind, primary prevention studies investi- gating a putative prevention of cancer by vitamins and trace elements. A mixture of selenium, vitamin E, and β-carotene, called factor D, signiﬁcantly reduced total mortality, total cancer mortality, and most signiﬁcantly mortality from gastric cancer [1]. Although selenium was not given as a single component, according to subsequent studies it appeared to have the most eﬃcient eﬀects [2–4]. 10 years after completion of the Linxian trial, reduction in mortality remained 5% for total and 11% for gastric cancer [5]. Considering age, the eﬀect of factor D was much stronger in individuals younger than 55 but almost absent in subjects older than 55 years. The eﬀect on esophageal cancer was even reversed by age [5]. The ﬁndings may indicate that selenium supplementation is only helpful to rescue a marginal deﬁ- ciency and that a beneﬁt of the supplementation depends on the stage of carcinogenesis. Whereas selenium appears to prevent initiation of cancer in healthy cells at young age, in the elderly it may be harmful and rather support tumor growth of already initiated cells [5]. Nrf2 as regulator of the endogenous response system has generally been considered as beneﬁcial, too. Since two seleno- proteins, thioredoxin reductase-1 (TrxR1) and glutathione peroxidase-2 (GPx2), are induced by Nrf2, a synergism of both systems has been proposed [6]. Whereas this might hold