title: Conditional expression of 15-lipoxygenase-1 inhibits the selenoenzyme thioredoxin reductase: modulation of selenoproteins by lipoxygenase enzymes.
abstract: The selenoenzyme thioredoxin reductase regulates redox-sensitive proteins involved in inflammation and carcinogenesis, including ribonucleotide reductase, p53, NFkappaB, and others. Little is known about endogenous cellular factors that modulate thioredoxin reductase activity. Here we report that several metabolites of 15-lipoxygenase-1 inhibit purified thioredoxin reductase in vitro. 15(S)-Hydroperoxy-5,8,11-cis-13-trans-eicosatetraenoic acid, a metastable hydroperoxide generated by 15-lipoxygenase-1, and 4-hydroxy-2-nonenal, its non-enzymatic rearrangement product inhibit thioredoxin reductase with IC(50) = 13 +/- 1.5 microm and 1 +/- 0.2 microm, respectively. Endogenously generated metabolites of 15-lipoxygenase-1 also inhibit thioredoxin reductase in HEK-293 cells that harbor a 15-LOX-1 gene under the control of an inducible promoter complex. Conditional, highly selective induction of 15-lipoxygenase-1 caused an inhibition of ribonucleotide reductase activity, cell cycle arrest in G(1), impairment of anchorage-independent growth, and accumulation of the pro-apoptotic protein BAX. All of these responses are consistent with inhibition of thioredoxin reductase via 15-lipoxygenase-1 overexpression. In contrast, metabolites of 5-lipoxygenase were poor inhibitors of isolated thioredoxin reductase, and the overexpression of 5-lipoxygenase did not inhibit thioredoxin reductase or cause a G cell cycle arrest. The influences of 15-lipoxygenase-1 on (1)inflammation, cell growth, and survival may be attributable, in part, to inhibition of thioredoxin reductase and several redox-sensitive processes subordinate to thioredoxin reductase.
authors.affiliation: Department of Internal Medicine, The Huntsman Cancer Institute, University of Utah Health Sciences, Salt Lake City, UT 84112-0555, USA.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Yu
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Moos
authors.forename: Pamela
authors.initials: P
authors.lastname: Cassidy
authors.forename: Mark
authors.initials: M
authors.lastname: Wade
authors.forename: F A
authors.initials: FA
authors.lastname: Fitzpatrick
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D017209:Apoptosis; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis*; D015153:Blotting, Western; D002384:Catalysis; D002448:Cell Adhesion; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D007700:Kinetics; D015289:Leukotrienes / Q000737:chemistry; D008054:Lipid Peroxides / Q000737:chemistry; D008084:Lipoxygenase / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000378:metabolism; D051140:Selenoproteins; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein
chemical_list: D000447:Aldehydes; C494826:BAX protein, human; D015289:Leukotrienes; D008054:Lipid Peroxides; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051140:Selenoproteins; D051028:bcl-2-Associated X Protein; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; D008084:Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D012264:Ribonucleotide Reductases; D013880:Thioredoxin-Disulfide Reductase; C027576:4-hydroxy-2-nonenal