This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gallegos, A. Articles by Powis, G. Search for Related Content PubMed PubMed Citation Articles by Gallegos, A. Articles by Powis, G.

Mechanisms of the Regulation of Thioredoxin Reductase Activity in Cancer Cells by the Chemopreventive Agent Selenium¹

Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724-5024

Selenium is an essential trace element, the deficiency of which is associated with an increased incidence of some human cancers. Dietary supplementation with selenium has been reported to produce a decrease in the incidence of some cancers in humans. Thioredoxin reductase (TR) is a newly discovered homodimeric selenocysteine (SeCys)-containing protein that catalyzes the NADPH-dependent reduction of the redox protein thioredoxin (Trx). Trx is overexpressed by a number of human tumors, and experimental studies have shown that Trx contributes to the growth and to the transformed phenotype of some human cancer cells. Thus, TR, by reducing Trx, could play a role in regulating the growth of normal and cancer cells. We have investigated mechanisms by which selenium, in the form of sodium selenite, added to serum-free growth medium regulates TR activity in cancer cell lines. Selenium caused a dose-dependent increase in cellular TR activity. The increase in TR activity produced by 1 µM Se compared to medium with no added selenium was: for MCF-7 breast cancer cells, 37-fold; for HT-29 colon cancer cells, 19-fold; and for A549 lung cancer cells, 8-fold. In contrast, Jurkat and HL-60 leukemia cells showed no increase in TR activity. The half-life of the time course of induction of TR in HT-29 cells after adding selenium was 10 h. The increase in TR activity was accompanied by an increase in TR protein levels up to 3-fold and an increase in the specific activity of the enzyme of 5–32-fold, depending on the cell line. Studies using ⁷⁵Se showed that the amount of selenium incorporated into TR increased with increasing selenium concentration up to a ratio of 1 selenium per TR monomer. There was an increase in TR mRNA levels of 2–5-fold at 1 µM selenium and an increase in the stability of TR mRNA with a half-life for degradation of 21 h compared to 10 h in the absence of selenium. Trx mRNA and protein levels and Trx mRNA stability were not affected by selenium. The results of the study show that the increase in TR activity caused by selenium is specific and due to several effects, including an increase in the stability of TR mRNA leading to increased TR mRNA levels, an increase in TR protein, but predominantly to an increase in the specific activity of TR associated with increased incorporation of selenium into the enzyme.

¹ Supported by NIH Grant CA48725 and a V Foundation Award.

² To whom requests for reprints should be addressed, at Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724-5024. Phone: (520) 626-6408; Fax: (520) 626-4848.

Received 7/ 1/97. Accepted 9/22/97.

This article has been cited by other articles:

				D. N. Stemm, J. C. Tharappel, H.-J. Lehmler, C. Srinivasan, J. S. Morris, V. L. Spate, L. W. Robertson, B. T. Spear, and H. P. Glauert Effect of Dietary Selenium on the Promotion of Hepatocarcinogenesis by 3,3', 4,4'-Tetrachlorobiphenyl and 2,2', 4,4', 5,5'-Hexachlorobiphenyl Experimental Biology and Medicine, March 1, 2008; 233(3): 366 - 376. [Abstract] [Full Text] [PDF]

				S. T. Miorelli, R. M. Rosa, D. J. Moura, J. C. Rocha, L. A. Carneiro Lobo, J. A. Pegas Henriques, and J. Saffi Antioxidant and anti-mutagenic effects of ebselen in yeast and in cultured mammalian V79 cells Mutagenesis, March 1, 2008; 23(2): 93 - 99. [Abstract] [Full Text] [PDF]

				N. Karunasinghe, L. R. Ferguson, J. Tuckey, and J. Masters Hemolysate Thioredoxin Reductase and Glutathione Peroxidase Activities Correlate with Serum Selenium in a Group of New Zealand Men at High Prostate Cancer Risk J. Nutr., August 1, 2006; 136(8): 2232 - 2235. [Abstract] [Full Text] [PDF]

				J. Kohrle, F. Jakob, B. Contempre, and J. E. Dumont Selenium, the Thyroid, and the Endocrine System Endocr. Rev., December 1, 2005; 26(7): 944 - 984. [Abstract] [Full Text] [PDF]

				S. O. Lee, N. Nadiminty, X. X. Wu, W. Lou, Y. Dong, C. Ip, S. A. Onate, and A. C. Gao Selenium Disrupts Estrogen Signaling by Altering Estrogen Receptor Expression and Ligand Binding in Human Breast Cancer Cells Cancer Res., April 15, 2005; 65(8): 3487 - 3492. [Abstract] [Full Text] [PDF]

				P. R. Taylor, H. L. Parnes, and S. M. Lippman Science Peels the Onion of Selenium Effects on Prostate Carcinogenesis J Natl Cancer Inst, May 5, 2004; 96(9): 645 - 647. [Full Text] [PDF]

				J. Zhang, V. Svehlikova, Y. Bao, A.F. Howie, G. J. Beckett, and G. Williamson Synergy between sulforaphane and selenium in the induction of thioredoxin reductase 1 requires both transcriptional and translational modulation Carcinogenesis, March 1, 2003; 24(3): 497 - 503. [Abstract] [Full Text] [PDF]

				P. J. Moos, K. Edes, P. Cassidy, E. Massuda, and F. A. Fitzpatrick Electrophilic Prostaglandins and Lipid Aldehydes Repress Redox-sensitive Transcription Factors p53 and Hypoxia-inducible Factor by Impairing the Selenoprotein Thioredoxin Reductase J. Biol. Chem., January 3, 2003; 278(2): 745 - 750. [Abstract] [Full Text] [PDF]

				W. Zhong and T. D. Oberley Redox-mediated Effects of Selenium on Apoptosis and Cell Cycle in the LNCaP Human Prostate Cancer Cell Line Cancer Res., October 1, 2001; 61(19): 7071 - 7078. [Abstract] [Full Text] [PDF]

				H. E. Ganther and C. Ip Thioredoxin Reductase Activity in Rat Liver Is Not Affected by Supranutritional Levels of Monomethylated Selenium In Vivo and Is Inhibited Only by High Levels of Selenium In Vitro J. Nutr., February 1, 2001; 131(2): 301 - 304. [Abstract] [Full Text]

				H. E. Ganther Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase Carcinogenesis, September 1, 1999; 20(9): 1657 - 1666. [Abstract] [Full Text] [PDF]

				M. Hotta, F. Tashiro, H. Ikegami, H. Niwa, T. Ogihara, J. Yodoi, and J.-i. Miyazaki Pancreatic beta  Cell-specific Expression of  Thioredoxin, an Antioxidative and Antiapoptotic Protein, Prevents Autoimmune and Streptozotocin-induced Diabetes J. Exp. Med., October 19, 1998; 188(8): 1445 - 1451. [Abstract] [Full Text] [PDF]

				S. N. Gorlatov and T. C. Stadtman Human thioredoxin reductase from HeLa cells: Selective alkylation of selenocysteine in the protein inhibits enzyme activity and reduction with NADPH influences affinity to heparin PNAS, July 21, 1998; 95(15): 8520 - 8525. [Abstract] [Full Text] [PDF]

				L. Zhong and A. Holmgren Essential Role of Selenium in the Catalytic Activities of Mammalian Thioredoxin Reductase Revealed by Characterization of Recombinant Enzymes with Selenocysteine Mutations J. Biol. Chem., June 9, 2000; 275(24): 18121 - 18128. [Abstract] [Full Text] [PDF]