title: Thioredoxin reductase, a redox-active selenoprotein, is secreted by normal and neoplastic cells: presence in human plasma.
abstract: Thioredoxin (Trx) and Trx reductase (TrxR) are redox-active proteins that participate in multiple cellular events, including growth promotion, apoptosis, and cytoprotection. Studies on overexpression of Trx and TrxR in human cancers have indicated a role of these proteins in tumor development. In this study, we analyzed the expression of TrxR in peripheral blood cells, tumor-transformed leukemia, and melanoma cells and found, in addition to abundant plasma membrane localization, that TrxR was released from these cells. Secretory cells were observed at the single cell level using a sensitive enzyme-linked immunospot assay. The release was inducible, and physiological stimulation of human monocytes by IFN-gamma, lipopolysaccharide, and interleukin 1alpha significantly increased the number of TrxR-secreting cells (P = 0.004). Secretion of TrxR followed the classical Golgi pathway, and it was confirmed by metabolic labeling using [35S]methionine and [35S]cysteine. TrxR was also detected for the first time in fresh healthy blood donor plasma (n = 21; median concentration, 18.0 ng/ml), with biological activity as determined by insulin reduction assay. These results highlight the role of extracellular Trx and TrxR during inflammation and tumor progression. Released Trx, with its active site motif containing amino acids Cys-X-X-Cys, was recently shown to have chemoattractant properties beside its previously described antioxidant and cocytokine activities. Regeneration of oxidized Trx requires available TrxR outside the cell, the presence and induction of which is described in this paper for normal and transformed cells.
authors.affiliation: Department of Biomedicine and Surgery, University of Linköping, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Söderberg
authors.forename: B
authors.initials: B
authors.lastname: Sahaf
authors.forename: A
authors.initials: A
authors.lastname: Rosén
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007938:Leukemia / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051140:Selenoproteins; D018038:Sodium Selenite / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000097:blood* / Q000737:chemistry / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D007328:Insulin; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011506:Proteins; D017382:Reactive Oxygen Species; D051140:Selenoproteins; D013879:Thioredoxins; D007371:Interferon-gamma; D013880:Thioredoxin-Disulfide Reductase; D018038:Sodium Selenite