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PLOS ONE  2008 

Cell Death by SecTRAPs: Thioredoxin Reductase as a Prooxidant Killer of Cells

DOI: 10.1371/journal.pone.0001846

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Abstract:

Background SecTRAPs (selenium compromised thioredoxin reductase-derived apoptotic proteins) can be formed from the selenoprotein thioredoxin reductase (TrxR) by targeting of its selenocysteine (Sec) residue with electrophiles, or by its removal through C-terminal truncation. SecTRAPs are devoid of thioredoxin reductase activity but can induce rapid cell death in cultured cancer cell lines by a gain of function. Principal Findings Both human and rat SecTRAPs killed human A549 and HeLa cells. The cell death displayed both apoptotic and necrotic features. It did not require novel protein synthesis nor did it show extensive nuclear fragmentation, but it was attenuated by use of caspase inhibitors. The redox active disulfide/dithiol motif in the N-terminal domain of TrxR had to be maintained for manifestation of SecTRAP cytotoxicity. Stopped-flow kinetics showed that NADPH can reduce the FAD moiety in SecTRAPs at similar rates as in native TrxR and purified SecTRAPs could maintain NADPH oxidase activity, which was accelerated by low molecular weight substrates such as juglone. In a cellular context, SecTRAPs triggered extensive formation of reactive oxygen species (ROS) and consequently antioxidants could protect against the cell killing by SecTRAPs. Conclusions We conclude that formation of SecTRAPs could contribute to the cytotoxicity seen upon exposure of cells to electrophilic agents targeting TrxR. SecTRAPs are prooxidant killers of cells, triggering mechanisms beyond those of a mere loss of thioredoxin reductase activity.

References

[1]  Tamura T, Stadtman TC (1996) A new selenoprotein from human lung adenocarcinoma cells: Purification, properties, and thioredoxin reductase activity. Proc Natl Acad Sci USA 93: 1006–1011.
[2]  Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, et al. (2003) Characterization of mammalian selenoproteomes. Science 300: 1439–1443.
[3]  Zhong L, Arnér ESJ, Ljung J, ?slund F, Holmgren A (1998) Rat and calf thioredoxin reductase are homologous to glutathione reductase with a carboxyl-terminal elongation containing a conserved catalytically active penultimate selenocysteine residue. J Biol Chem 273: 8581–8591.
[4]  Lillig CH, Holmgren A (2007) Thioredoxin and related molecules-from biology to health and disease. Antioxid Redox Signal 9: 25–47.
[5]  Arnér ESJ, Holmgren A (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267: 6102–6109.
[6]  Gromer S, Urig S, Becker K (2004) The thioredoxin system–from science to clinic. Med Res Rev 24: 40–89.
[7]  Nakamura H, Nakamura K, Yodoi J (1997) Redox regulation of cellular activation. Annu Rev Immunol 15: 351–369.
[8]  Nordberg J, Arnér ESJ (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 31: 1287–1312.
[9]  Rundl?f A-K, Arnér ESJ (2004) Regulation of the mammalian selenoprotein thioredoxin reductase 1 in relation to cellular phenotype, growth and signaling events. Antiox Redox Signal 6: 41–52.
[10]  Lee SR, Kim JR, Kwon KS, Yoon HW, Levine RL, et al. (1999) Molecular cloning and characterization of a mitochondrial selenocysteine-containing thioredoxin reductase from rat liver. J Biol Chem 274: 4722–4734.
[11]  Miranda-Vizuete A, Damdimopoulos AE, Pedrajas JR, Gustafsson JA, Spyrou G (1999) Human mitochondrial thioredoxin reductase cDNA cloning, expression and genomic organization. Eur J Biochem 261: 405–412.
[12]  Rigobello MP, Callegaro MT, Barzon E, Benetti M, Bindoli A (1998) Purification of mitochondrial thioredoxin reductase and its involvement in the redox regulation of membrane permeability. Free Radic Biol Med 24: 370–376.
[13]  Sun QA, Kirnarsky L, Sherman S, Gladyshev VN (2001) Selenoprotein oxidoreductase with specificity for thioredoxin and glutathione systems. Proc Nat'l Acad Sci USA 98: 3673–3678.
[14]  Su D, Novoselov SV, Sun QA, Moustafa ME, Zhou Y, et al. (2005) Mammalian selenoprotein thioredoxin-glutathione reductase. Roles in disulfide bond formation and sperm maturation. J Biol Chem 280: 26491–26498.
[15]  Sandalova T, Zhong L, Lindqvist Y, Holmgren A, Schneider G (2001) Three-dimensional structure of a mammalian thioredoxin reductase: Implications for mechanism and evolution of a selenocysteine-dependent enzyme. Proc Nat'l Acad Sci USA 98: 9533–9538.
[16]  Biterova EI, Turanov AA, Gladyshev VN, Barycki JJ (2005) Crystal structures of oxidized and reduced mitochondrial thioredoxin reductase provide molecular details of the reaction mechanism. Proc Natl Acad Sci U S A 102: 15018–15023.
[17]  Zhong L, Arnér ESJ, Holmgren A (2000) Structure and mechanism of mammalian thioredoxin reductase: The active site is a redox-active selenolthiol/selenenylsulfide formed from the conserved cysteine-selenocysteine sequence. Proc Natl Acad Sci USA 97: 5854–5859.
[18]  Lee SR, Bar-Noy S, Kwon J, Levine RL, Stadtman TC, et al. (2000) Mammalian thioredoxin reductase: oxidation of the C-terminal cysteine/selenocysteine active site forms a thioselenide, and replacement of selenium with sulfur markedly reduces catalytic activity. Proc Natl Acad Sci USA 97: 2521–2526.
[19]  Arscott LD, Gromer S, Schirmer RH, Becker K, Williams CH Jr (1997) The mechanism of thioredoxin reductase from human placenta is similar to the mechanisms of lipoamide dehydrogenase and glutathione reductase and is distinct from the mechanism of thioredoxin reductase from Escherichia coli. Proc Natl Acad Sci U S A 94: 3621–3626.
[20]  Zhong L, Holmgren A (2000) Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations. J Biol Chem 275: 18121–18128.
[21]  Lundstr?m-Ljung J, Birnbach U, Rupp K, Soling HD, Holmgren A (1995) Two resident ER-proteins, CaBP1 and CaBP2, with thioredoxin domains, are substrates for thioredoxin reductase: comparison with protein disulfide isomerase. FEBS Lett 357: 305–308.
[22]  Andersson M, Holmgren A, Spyrou G (1996) NK-lysin, a disulfide-containing effector peptide of T-lymphocytes, is reduced and inactivated by human thioredoxin reductase. Implication for a protective mechanism against NK-lysin cytotoxicity. J Biol Chem 271: 10116–10120.
[23]  Kumar S, Bj?rnstedt M, Holmgren A (1992) Selenite is a substrate for calf thymus thioredoxin reductase and thioredoxin and elicits a large non-stoichiometric oxidation of NADPH in the presence of oxygen. Eur J Biochem 207: 435–439.
[24]  Arnér ESJ, Nordberg J, Holmgren A (1996) Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase. Biochem Biophys Res Commun 225: 268–274.
[25]  May JM, Mendiratta S, Hill KE, Burk RF (1997) Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. J Biol Chem 272: 22607–22610.
[26]  Xia L, Nordman T, Olsson JM, Damdimopoulos A, Bj?rkhem-Bergman L, et al. (2003) The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. J Biol Chem 278: 2141–2146.
[27]  Cenas N, Nivinskas H, Anusevicius Z, Sarlauskas J, Lederer F, et al. (2004) Interactions of quinones with thioredoxin reductase—A challenge to the antioxidant role of the mammalian selenoprotein. J Biol Chem 279: 2583–2592.
[28]  Johansson L, Gafvelin G, Arnér ESJ (2005) Selenocysteine in proteins—properties and biotechnological use. Biochim Biophys Acta 1726: 1–13.
[29]  Gromer S, Arscott LD, Williams CH, Schirmer RH, Becker K (1998) Human placenta thioredoxin reductase: Isolation of the selenoenzyme, steady state kinetics, and inhibition by therapeutic gold compounds. J Biol Chem 273: 20096–20101.
[30]  Lu J, Chew EH, Holmgren A (2007) Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci U S A 104: 12288–12293.
[31]  Arnér ESJ, Nakamura H, Sasada T, Yodoi J, Holmgren A, et al. (2001) Analysis of the inhibition of mammalian thioredoxin, thioredoxin reductase, and glutaredoxin by cis-diamminedichloroplatinum (II) and its major metabolite, the glutathione-platinum complex. Free Radic Biol Med 31: 1170–1178.
[32]  Becker K, Herold-Mende C, Park JJ, Lowe G, Schirmer RH (2001) Human thioredoxin reductase is efficiently inhibited by (2,2′:6′,2′ ′-terpyridine)platinum(II) complexes. Possible implications for a novel antitumor strategy. J Med Chem 44: 2784–2792.
[33]  Sasada T, Nakamura H, Ueda S, Sato N, Kitaoka Y, et al. (1999) Possible involvement of thioredoxin reductase as well as thioredoxin in cellular sensitivity to cis-diamminedichloroplatinum (II). Free Radic Biol Med 27: 504–514.
[34]  Witte AB, Anest?l K, Jerremalm E, Ehrsson H, Arnér ESJ (2005) Inhibition of thioredoxin reductase but not of glutathione reductase by the major classes of alkylating and platinum-containing anticancer compounds. Free Radic Biol Med 39: 696–703.
[35]  Gromer S, Schirmer RH, Becker K (1997) The 58 kDa mouse selenoprotein is a BCNU-sensitive thioredoxin reductase. FEBS Lett 412: 318–320.
[36]  Moos PJ, Edes K, Cassidy P, Massuda E, Fitzpatrick FA (2003) Electrophilic prostaglandins and lipid aldehydes repress redox-sensitive transcription factors p53 and hypoxia-inducible factor by impairing the selenoprotein thioredoxin reductase. J Biol Chem 278: 745–750.
[37]  Anest?l K, Arnér ESJ (2003) Rapid Induction of Cell Death by Selenium-compromised Thioredoxin Reductase 1 but Not by the Fully Active Enzyme Containing Selenocysteine. J Biol Chem 278: 15966–15972.
[38]  Lindner DJ, Hofmann ER, Karra S, Kalvakolanu DV (2000) The interferon-beta and tamoxifen combination induces apoptosis using thioredoxin reductase. Biochim Biophys Acta 1496: 196–206.
[39]  Lindner DJ, Ma X, Hu J, Karra S, Kalvakolanu DV (2002) Thioredoxin Reductase Plays a Critical Role in IFN Retinoid-mediated Tumor-Growth Control in Vivo. Clin Cancer Res 8: 3210–3218.
[40]  Hofman ER, Boyanapalli M, Lindner DJ, Weihua X, Hassel BA, et al. (1998) Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid. Mol Cell Biol 18: 6493–6504.
[41]  Ma X, Hu J, Lindner DJ, Kalvakolanu DV (2002) Mutational analysis of human thioredoxin reductase 1. Effects on p53-mediated gene expression and interferon and retinoic acid-induced cell death. J Biol Chem 277: 22460–22468.
[42]  Ma X, Karra S, Guo W, Lindner DJ, Hu J, et al. (2001) Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase. J Biol Chem 276: 24843–24854.
[43]  Arnér ESJ, Sarioglu H, Lottspeich F, Holmgren A, B?ck A (1999) High-level expression in Escherichia coli of selenocysteine-containing rat thioredoxin reductase utilizing gene fusions with engineered bacterial-type SECIS elements and co-expression with the selA, selB and selC genes. J Mol Biol 292: 1003–1016.
[44]  Rengby O, Johansson L, Carlson LA, Serini E, Vlamis-Gardikas A, et al. (2004) Assessment of Production Conditions for Efficient Use of Escherichia coli in High-Yield Heterologous Recombinant Selenoprotein Synthesis. Appl Environ Microbiol 70: 5159–5167.
[45]  Johansson L, Chen C, Thorell J-O, Fredriksson A, Stone-Elander S, et al. (2004) Exploiting the 21st amino acid-purifying and labeling proteins by selenolate targeting. Nat Methods 1: 61–66.
[46]  Cheng Q, Stone-Elander S, Arnér ESJ (2006) Tagging recombinant proteins with a Sel-tag for purification, labeling with electrophilic compounds or radiolabeling with carbon-11. Nat Protocols 1: 604–613.
[47]  Rundl?f A-K, Janard M, Miranda-Vizuete A, Arnér ESJ (2004) Evidence for intriguingly complex transcription of human thioredoxin reductase 1. Free Rad Biol Med 36: 641–656.
[48]  Chung CT, Niemela SL, Miller RH (1989) One-step preparation of competent Escherichia coli: transformation and storage of bacterial cells in the same solution. Proc Natl Acad Sci 86: 2172–2175.
[49]  Rengby O, Arnér ESJ (2007) Titration and conditional knockdown of the prfB gene in Escherichia coli: effects on growth and overproduction of the recombinant mammalian selenoprotein thioredoxin reductase. Appl Environ Microbiol 73: 432–441.
[50]  Arnér ESJ, Holmgren A (2000) Measurement of thioredoxin and thioredoxin reductase. In: Maines M, Costa L, Reed D, Sassa S, editors. Current Protocols in Toxicology. New York: John Wiley & Sons, Inc. pp. 7.4.1–7.4.14.
[51]  Nordberg J, Zhong L, Holmgren A, Arnér ESJ (1998) Mammalian thioredoxin reductase is irreversibly inhibited by dinitrohalobenzenes by alkylation of both the redox active selenocysteine and its neighboring cysteine residue. J Biol Chem 273: 10835–10842.
[52]  Cenas N, Prast S, Nivinskas H, Sarlauskas J, Arnér ESJ (2006) Interactions of nitroaromatic compounds with the mammalian selenoprotein thioredoxin reductase and the relation to induction of apoptosis in human cancer cells. J Biol Chem 281: 5593–5603.
[53]  Arnér ESJ (2002) Recombinant expression of mammalian selenocysteine-containing thioredoxin reductase and other selenoproteins in Escherichia coli. Methods Enzymol 347: 226–235.
[54]  Bar-Noy S, Gorlatov SN, Stadtman TC (2001) Overexpression of wild type and SeCys/Cys mutant of human thioredoxin reductase in E. coli: the role of selenocysteine in the catalytic activity. Free Radic Biol Med 30: 51–61.
[55]  Turanov AA, Su D, Gladyshev VN (2006) Characterization of alternative cytosolic forms and cellular targets of mouse mitochondrial thioredoxin reductase. J Biol Chem 281: 22953–22963.
[56]  Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, et al. (2004) A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science 305: 1471–1474.
[57]  Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326 ( Pt 1): 1–16.
[58]  Fadeel B, Orrenius S, Zhivotovsky B (2000) The most unkindest cut of all: on the multiple roles of mammalian caspases. Leukemia 14: 1514–1525.
[59]  Marzano C, Gandin V, Folda A, Scutari G, Bindoli A, et al. (2007) Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells. Free Radic Biol Med 42: 872–881.
[60]  Cassidy PB, Edes K, Nelson CC, Parsawar K, Fitzpatrick FA, et al. (2006) Thioredoxin reductase is required for the inactivation of tumor suppressor p53 and for apoptosis induced by endogenous electrophiles. Carcinogenesis 27: 2538–2549.
[61]  Berndtsson M, Hagg M, Panaretakis T, Havelka AM, Shoshan MC, et al. (2007) Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA. Int J Cancer 120: 175–180.
[62]  Fang J, Lu J, Holmgren A (2005) Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. J Biol Chem 280: 25284–25290.
[63]  Fang J, Holmgren A (2006) Inhibition of thioredoxin and thioredoxin reductase by 4-hydroxy-2-nonenal in vitro and in vivo. J Am Chem Soc 128: 1879–1885.
[64]  Urig S, Becker K (2006) On the potential of thioredoxin reductase inhibitors for cancer therapy. Semin Cancer Biol 16: 452–465.
[65]  Becker K, Gromer S, Schirmer RH, Müller S (2000) Thioredoxin reductase as a pathophysiological factor and drug target. Eur J Biochem 267: 6118–6125.
[66]  Arner ES, Holmgren A (2006) The thioredoxin system in cancer. Semin Cancer Biol 16: 420–426.
[67]  Yoo MH, Xu XM, Carlson BA, Patterson AD, Gladyshev VN, et al. (2007) Targeting thioredoxin reductase 1 reduction in cancer cells inhibits self-sufficient growth and DNA replication. PLoS ONE 2: e1112.
[68]  Yoo MH, Xu XM, Carlson BA, Gladyshev VN, Hatfield DL (2006) Thioredoxin reductase 1 deficiency reverses tumor phenotype and tumorigenicity of lung carcinoma cells. J Biol Chem 281: 13005–13008.
[69]  Watson WH, Heilman JM, Hughes LL, Spielberger JC (2008) Thioredoxin reductase-1 knock down does not result in thioredoxin-1 oxidation. Biochem Biophys Res Commun.
[70]  Urig S, Lieske J, Fritz-Wolf K, Irmler A, Becker K (2006) Truncated mutants of human thioredoxin reductase 1 do not exhibit glutathione reductase activity. FEBS Lett 580: 3595–3600.
[71]  Yarimizu J, Nakamura H, Yodoi J, Takahashi K (2000) Efficiency of selenocysteine incorporation in human thioredoxin reductase. Antioxid Redox Signal 2: 643–651.
[72]  Crosley LK, Meplan C, Nicol F, Rundl?f A-K, Arnér ES, et al. (2007) Differential regulation of expression of cytosolic and mitochondrial thioredoxin reductase in rat liver and kidney. Arch Biochem Biophys 459: 178–188.
[73]  Nalvarte I, Damdimopoulos AE, Nystr?m C, Nordman T, Miranda-Vizuete A, et al. (2004) Overexpression of enzymatically active human cytosolic and mitochondrial thioredoxin reductase in HEK-293 cells. Effect on cell growth and differentiation. J Biol Chem 279: 54510–54517.
[74]  Trigona WL, Mullarky IK, Cao Y, Sordillo LM (2006) Thioredoxin reductase regulates the induction of haem oxygenase-1 expression in aortic endothelial cells. Biochem J 394: 207–216.
[75]  Gan L, Yang XL, Liu Q, Xu HB (2005) Inhibitory effects of thioredoxin reductase antisense RNA on the growth of human hepatocellular carcinoma cells. J Cell Biochem 96: 653–664.
[76]  Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, et al. (2007) Mechanisms of cell death in oxidative stress. Antioxid Redox Signal 9: 49–89.
[77]  Enoksson M, Robertson JD, Gogvadze V, Bu P, Kropotov A, et al. (2004) Caspase-2 permeabilizes the outer mitochondrial membrane and disrupts the binding of cytochrome c to anionic phospholipids. J Biol Chem 279: 49575–49578.
[78]  Robertson JD, Gogvadze V, Kropotov A, Vakifahmetoglu H, Zhivotovsky B, et al. (2004) Processed caspase-2 can induce mitochondria-mediated apoptosis independently of its enzymatic activity. EMBO Rep 5: 643–648.
[79]  Schweizer A, Roschitzki-Voser H, Amstutz P, Briand C, Gulotti-Georgieva M, et al. (2007) Inhibition of caspase-2 by a designed ankyrin repeat protein: specificity, structure, and inhibition mechanism. Structure 15: 625–636.

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