title: Thioredoxin reductase 1 deficiency enhances selenite toxicity in cancer cells via a thioredoxin-independent mechanism.
abstract: Selenium is an essential trace element in mammals, but is toxic at high levels. It is best known for its cancer prevention activity, but cancer cells are more sensitive to selenite toxicity than normal cells. Since selenite treatment leads to oxidative stress, and the Trx (thioredoxin) system is a major antioxidative system, we examined the interplay between TR1 (Trx reductase 1) and Trx1 deficiencies and selenite toxicity in DT cells, a malignant mouse cell line, and the corresponding parental NIH 3T3 cells. TR1-deficient cells were far more sensitive to selenite toxicity than Trx1-deficient or control cells. In contrast, this effect was not seen in cells treated with hydrogen peroxide, suggesting that the increased sensitivity of TR1 deficiency to selenite was not due to oxidative stress caused by this compound. Further analyses revealed that only TR1-deficient cells manifested strongly enhanced production and secretion of glutathione, which was associated with increased sensitivity of the cells to selenite. The results suggest a new role for TR1 in cancer that is independent of Trx reduction and compensated for by the glutathione system. The results also suggest that the enhanced selenite toxicity of cancer cells and simultaneous inhibition of TR1 can provide a new avenue for cancer therapy.
authors.affiliation: Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Tobe
authors.forename: Min-Hyuk
authors.initials: MH
authors.lastname: Yoo
authors.forename: Noelia
authors.initials: N
authors.lastname: Fradejas
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.forename: Soledad
authors.initials: S
authors.lastname: Calvo
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.forename: Dolph L
authors.initials: DL
authors.lastname: Hatfield
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D018038:Sodium Selenite / Q000494:pharmacology*; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D034741:RNA, Small Interfering; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D005978:Glutathione; D018038:Sodium Selenite