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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Loss of thioredoxin reductase 1 renders tumors highly susceptible to pharmacologic glutathione deprivation.
Cancer Res. 70, 9505-9514 (2010)
Tumor cells generate substantial amounts of reactive oxygen species (ROS), engendering the need to maintain high levels of antioxidants such as thioredoxin (Trx)- and glutathione (GSH)-dependent enzymes. Exacerbating oxidative stress by specifically inhibiting these types of ROS-scavenging enzymes has emerged as a promising chemotherapeutic strategy to kill tumor cells. However, potential redundancies among the various antioxidant systems may constrain this simple approach. Trx1 and thioredoxin reductase 1 (Txnrd1) are up-regulated in numerous cancers, and Txnrd1 has been reported to be indispensable for tumorigenesis. However, we report here that genetic ablation of Txnrd1 has no apparent effect on tumor cell behavior based on similar proliferative, clonogenic, and tumorigenic potential. This finding reflects widespread redundancies between the Trx- and GSH-dependent systems based on evidence of a bypass to Txnrd1 deficiency by compensatory upregulation of GSH-metabolizing enzymes. Because the survival and growth of Txnrd1-deficient tumors were strictly dependent on a functional GSH system, Txnrd1(-/-) tumors were highly susceptible to experimental GSH depletion in vitro and in vivo. Thus, our findings establish for the first time that a concomitant inhibition of the two major antioxidant systems is highly effective in killing tumor, highlighting a promising strategy to combat cancer.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
EARLY EMBRYONIC LETHALITY; NON-ONCOGENE ADDICTION; OXIDATIVE STRESS; CANCER-THERAPY; RIBONUCLEOTIDE REDUCTASE; OXIDIZED GLUTATHIONE; CARCINOMA CELLS; IN-VIVO; SYSTEM; GENE
ISSN (print) / ISBN
0008-5472
e-ISSN
1538-7445
Zeitschrift
Cancer Research
Quellenangaben
Band: 70,
Heft: 22,
Seiten: 9505-9514
Verlag
American Association for Cancer Research (AACR)
Verlagsort
Philadelphia, Pa.
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed