Journal Article

Thioredoxin reductase 1 protects against chemically induced hepatocarcinogenesis <i>via</i> control of cellular redox homeostasis

Bradley A. Carlson, Min-Hyuk Yoo, Ryuta Tobe, Charles Mueller, Salvador Naranjo-Suarez, Victoria J. Hoffmann, Vadim N. Gladyshev and Dolph L. Hatfield

in Carcinogenesis

Volume 33, issue 9, pages 1806-1813
Published in print September 2012 | ISSN: 0143-3334
Published online July 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs230
Thioredoxin reductase 1 protects against chemically induced hepatocarcinogenesis via control of cellular redox homeostasis

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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.

Abbreviations

AOX1

aldehyde oxygenase 1

CAT

catalase

CBR3

carbonyl reductase 3

DEN

diethylnitrosamine

GCLC

glutamate–cysteine ligase

GPx1

glutathione peroxidase 1

GPx2

glutathione peroxidase 2

GPx4

glutathione peroxidase 4

GSR

glutathione reductase

GST-α1

glutathione-S-transferase-alpha 1

GAPDH

glyceraldehyde 3-phosphate dehydrogenase

GSH

glutathione

mRNA

messenger RNA

MT1

metallothionein 1

PRDX1

peroxiredoxin 1

PB

phenobarbital

SRXN1

sulfiredoxin 1

SOD1

superoxide dismutase 1

TRX1

thioredoxin 1

TR1

thioredoxin reductase 1

Trx

Thioredoxin

Journal Article.  5859 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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