International Journal of Cell Biology that SFN needs a selenoprotein or a selenium-dependent process to act beneﬁcially. However, this protein cannot possibly be GPx2 since SFN eﬀects were the same in WT and GPx2 KO mice. The responsible selenoprotein might rather be GPx1 which is upregulated in the intestine of GPx2 KO mice [88], but can only be synthesized when selenium is available. Taken together, there is an interplay between selenium and Nrf2 activators, but this appears to be much more complex than a synergistic upregulation by Nrf2-mediated transcriptional activation and subsequent translation of a speciﬁc selenoprotein. In short, GPx2 appears to be a protective enzyme with pronounced anti-inﬂammatory potential and antiapoptotic capacity. Consequences of an upregulated GPx2 might, however, diﬀer between healthy and malignant tissue. In healthy tissue, GPx2 is required to maintain the normal self- renewing of the gastrointestinal epithelium and, as part of the adaptive response, to depress inﬂammatory processes. This way GPx2 can inhibit initiation of carcinogenesis. But once a cell has been programmed to proliferate in an uncontrolled way, GPx2, inter alia by inhibiting apoptosis, supports further growth, which does not appear particularly beneﬁcial. This view is in line with the clinical study described in the beginning which revealed a decrease of esophageal cancer incidence by selenium only in younger but not in older participants [5]. Similarly, in recent N- nitrosomethylbenzylamine-induced esophageal squamous cell carcinoma (ESCC) study, the numbers of dysplasia and ESCC were signiﬁcantly lower in rats on supplementation with selenium and vitamin E only during the early stage of tumor development or during the entire experimental period but not during the late stage [93]. 5. Conclusions The beneﬁt of upregulation/activation of the Nrf2 pathway of the selenoproteins TrxR1 and GPx2 diﬀers in healthy and in cancer cells. Via its physiological role in a program main- taining the cellular redox state and inter alia the endogenous defense systems and by preventing apoptosis and damage by a dysregulated redox homeostasis, Nrf2 might contribute to the prevention of cancer initiation in healthy cells. The vital function of TrxR1 is explained by its role in the replication and proliferation of developing healthy cells. The physiological function of GPx2 appears to support prolifera- tion of crypt base epithelial cells in the self-renewal of the gastrointestinal epithelium. Its antiapoptotic and anti- inﬂammatory properties might help to inhibit the initiation and promotion of carcinogenesis by proinﬂammatory medi- ators. However, if a cell has been transformed into a malignant cell and the carcinogenic process has started, the cancer cells will equally proﬁt from the protective roles of TrxR1, GPx2, and other Nrf2 programs and, accordingly, will grow unhampered. Acknowledgment This work was supported by the German Research Council (DFG) BR778/8-1. 5 References [1] W. J. Blot, J. Y. Li, P. R. Taylor et al., “Nutrition interven- tion trials in Linxian, China: supplementation with speciﬁc vitamin/mineral combinations, cancer incidence, and disease- speciﬁc mortality in the general population,” Journal of the National Cancer Institute, vol. 85, no. 18, pp. 1483–1492, 1993. [2] W. Q. Wei, C. C. Abnet, Y. L. Qiao et al., “Prospective study of serum selenium concentrations and esophageal and gastric cardia cancer, heart disease, stroke, and total death,” American Journal of Clinical Nutrition, vol. 79, no. 1, pp. 80–85, 2004. [3] S. D. Mark, Y. L. Qiao, S. M. Dawsey et al., “Prospective study of serum selenium levels and incident esophageal and gastric cancers,” Journal of the National Cancer Institute, vol. 92, no. 21, pp. 1753–1763, 2000. [4] J. Steevens, P. A. van den Brandt, R. A. Goldbohm, and L. J. Schouten, “Selenium status and the risk of esophageal and gastric cancer subtypes: the Netherlands cohort study,” Gastroenterology, vol. 138, no. 5, pp. 1704–1713, 2010. [5] Y. L. Qiao, S. M. Dawsey, F. Kamangar et al., “Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the linxian general population nutrition inter- vention trial,” Journal of the National Cancer Institute, vol. 101, no. 7, pp. 507–518, 2009. [6] R. Brigelius-Flohe´ and A. Banning, “Sulforaphane and sele- nium, partners in adaptive response and prevention of cancer,” Free Radical Research, vol. 40, no. 8, pp. 775–787, 2006. [7] A. Lau, N. F. Villeneuve, Z. Sun, P. K. Wong, and D. D. Zhang, “Dual roles of Nrf2 in cancer,” Pharmacological Research, vol. 58, no. 5-6, pp. 262–270, 2008. [8] T. W. Kensler and N. Wakabayashi, “Nrf2: friend or foe for chemoprevention?” Carcinogenesis, vol. 31, no. 1, Article ID bgp231, pp. 90–99, 2009. [9] R. Brigelius-Flohe´ and L. Flohe´, “Basic principles and emerg- ing concepts in the redox control of transcription factors,” Antioxidants and Redox Signaling, vol. 15, no. 8, pp. 2335– 2381, 2011. [10] W. Li and A. N. Kong, “Molecular mechanisms of Nrf2- mediated antioxidant response,” Molecular Carcinogenesis, vol. 48, no. 2, pp. 91–104, 2009. [11] S. K. Niture, J. W. Kaspar, J. Shen, and A. K. Jaiswal, “Nrf2 signaling and cell survival,” Toxicology and Applied Pharmacology, vol. 244, no. 1, pp. 37–42, 2010. [12] Y. J. Surh, J. K. Kundu, and H. K. Na, “Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals,” Planta Medica, vol. 74, no. 13, pp. 1526– 1539, 2008. [13] K. Itoh, J. Mimura, and M. Yamamoto, “Discovery of the negative regulator of Nrf2, keap1: a historical overview,” Antioxidants and Redox Signaling, vol. 13, no. 11, pp. 1665– 1678, 2010. [14] W. Chen, Z. Sun, X. J. Wang et al., “Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response,” Molecular Cell, vol. 34, no. 6, pp. 663– 673, 2009. [15] K. I. Tong, A. Kobayashi, F. Katsuoka, and M. Yamamoto, “Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism,” Biological Chemistry, vol. 387, no. 10-11, pp. 1311–1320, 2006. [16] A. L. Eggler, K. A. Gay, and A. D. Mesecar, “Molecular mech- anisms of natural products in chemoprevention: induction of cytoprotective enzymes by Nrf2,” Molecular Nutrition and Food Research, vol. 52, supplement 1, pp. S84–S94, 2008.