Thioredoxin reductase 1 protects against chemically induced hepatocarcinogenesis via control of cellular redox homeostasis.
Thioredoxin reductase 1 (TR1) controls the redox state of protein thiols in mammalian cells and has been shown to have roles in both preventing and promoting cancer. To define the role of this selenoenzyme in hepatocellular carcinoma development, we examined tumor incidence in the liver of mice with tissue-specific knockout of mouse TR1 subjected to the liver carcinogen, diethylnitrosamine (DEN). TR1-deficient livers manifested ~90% tumor incidence compared with ~16% in control livers. The TR1-dependent effect was observed independent of sex, and, in control mice, tumorigenesis did not affect the expression of TR1. On the other hand, we observed upregulation of another selenoenzyme, glutathione peroxidase 2 (GPx2), and components of the glutathione (GSH) system, including those that generate reduced GSH. Overall, this study shows that TR1 protects against chemically induced hepatocarcinogenesis via the control of the cellular redox state, whereas its role in promoting this type of cancer is minimal.
Molecular Biology of Selenium Section, Laboratory of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Bradley A
BA
Carlson
Min-Hyuk
MH
Yoo
Ryuta
R
Tobe
Charles
C
Mueller
Salvador
S
Naranjo-Suarez
Victoria J
VJ
Hoffmann
Vadim N
VN
Gladyshev
Dolph L
DL
Hatfield
D000818:Animals; D001835:Body Weight; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000032:analysis; D006706:Homeostasis; D008113:Liver Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010084:Oxidation-Reduction; D054481:Thioredoxin Reductase 1 / Q000502:physiology*; D000094765:Glutathione Peroxidase GPX1
D005979:Glutathione Peroxidase; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D005978:Glutathione; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse