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Mandal, P.K. ; Schneider, M.* ; Kölle, P.* ; Kuhlencordt, P.* ; Förster, H. ; Beck, H.* ; Bornkamm, G.W. ; Conrad, M.

Loss of thioredoxin reductase 1 renders tumors highly susceptible to pharmacologic glutathione deprivation.

Cancer Res. 70, 9505-9514 (2010)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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
Sprache englisch
Veröffentlichungsjahr 2010
HGF-Berichtsjahr 2010
ISSN (print) / ISBN 0008-5472
e-ISSN 1538-7445
Zeitschrift Cancer Research
Quellenangaben Band: 70, Heft: 22, Seiten: 9505-9514 Artikelnummer: , Supplement: ,
Verlag American Association for Cancer Research (AACR)
Verlagsort Philadelphia, Pa.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
Institute of Developmental Genetics (IDG)
POF Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30204 - Cell Programming and Repair
Forschungsfeld(er)
Immune Response and Infection
Genetics and Epidemiology
PSP-Element(e) G-501400-003
G-501400-006
G-500500-001
PubMed ID 21045148
DOI 10.1158/0008-5472.CAN-10-1509
Scopus ID 78549288556
Erfassungsdatum 2010-12-03
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