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TrxR1, Gsr, and oxidative stress determine hepatocellular carcinoma malignancy

Artikel i vetenskaplig tidskrift
Författare M. R. McLoughlin
D. J. Orlicky
J. R. Prigge
P. Krishna
E. A. Talago
I. R. Cavigli
S. Eriksson
C. G. Miller
J. A. Kundert
Volkan I. Sayin
R. A. Sabol
J. Heinemann
L. O. Brandenberger
S. V. Iverson
B. Bothner
T. Papagiannakopoulos
C. T. Shearn
E. S. J. Arner
E. E. Schmidt
Publicerad i Proceedings of the National Academy of Sciences of the United States of America
Volym 116
Nummer/häfte 23
Sidor 11408-11417
ISSN 0027-8424
Publiceringsår 2019
Publicerad vid Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Sidor 11408-11417
Språk en
Länkar dx.doi.org/10.1073/pnas.1903244116
Ämnesord thioredoxin reductase, glutathione reductase, Nrf2, oxidative stress, hepatocellular carcinoma, cytochrome-p450 induction, DNA-damage, cancer, nrf2, activation, glutathione, keap1, cells, expression, pathways
Ämneskategorier Cell- och molekylärbiologi, Cancer och onkologi

Sammanfattning

Thioredoxin reductase-1 (TrxR1)-, glutathione reductase (Gsr)-, and Nrf2 transcription factor-driven antioxidant systems form an integrated network that combats potentially carcinogenic oxidative damage yet also protects cancer cells from oxidative death. Here we show that although unchallenged wild-type (WT), TrxR1-null, or Gsr-null mouse livers exhibited similarly low DNA damage indices, these were 100-fold higher in unchallenged TrxR1/Gsr-double-null livers. Notwithstanding, spontaneous cancer rates remained surprisingly low in TrxR1/Gsr-null livers. All genotypes, including TrxR1/Gsr-null, were susceptible to N-diethylnitrosamine (DEN)-induced liver cancer, indicating that loss of these antioxidant systems did not prevent cancer cell survival. Interestingly, however, following DEN treatment, TrxR1-null livers developed threefold fewer tumors compared with WT livers. Disruption of TrxR1 in a marked subset of DEN-initiated cancer cells had no effect on their subsequent contributions to tumors, suggesting that TrxR1-disruption does not affect cancer progression under normal care, but does decrease the frequency of DEN-induced cancer initiation. Consistent with this idea, TrxR1-null livers showed altered basal and DEN-exposed metabolomic profiles compared with WT livers. To examine how oxidative stress influenced cancer progression, we compared DEN-induced cancer malignancy under chronically low oxidative stress (TrxR1-null, standard care) vs. elevated oxidative stress (TrxR1/Gsr-null livers, standard care or phenobarbital-exposed TrxR1-null livers). In both cases, elevated oxidative stress was correlated with significantly increased malignancy. Finally, although TrxR1-null and TrxR1/Gsr-null livers showed strong Nrf2 activity in noncancerous hepatocytes, there was no correlation between malignancy and Nrf2 expression within tumors across genotypes. We conclude that TrxR1, Gsr, Nrf2, and oxidative stress are major determinants of liver cancer but in a complex, context-dependent manner.

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