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

Abstract

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 upregulated 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.

• Authors: Pankaj Kumar Mandal, Manuela Schneider, Pirkko Kölle, Peter Kuhlencordt, Heidi Förster, Heike Beck, Georg W Bornkamm, Marcus Conrad
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 22 Pg. 9505-14 (Nov 15 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 21045148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 AACR.

Chemical References

• Membrane Proteins
• Heme Oxygenase-1
• Hmox1 protein, mouse
• Glutathione Reductase
• Thioredoxin Reductase 1
• Txnrd1 protein, mouse
• Glutathione Transferase
• Glutathione
• Glutathione Disulfide

Topics

• Animals
• Blotting, Western
• Cell Cycle
• Cell Line, Transformed
• Cell Proliferation
• Cells, Cultured
• Embryo, Mammalian (cytology)
• Female
• Fibroblasts (cytology, metabolism)
• Glutathione (metabolism)
• Glutathione Disulfide (metabolism)
• Glutathione Reductase (genetics, metabolism)
• Glutathione Transferase (genetics, metabolism)
• Heme Oxygenase-1 (genetics, metabolism)
• Lymphoma, B-Cell (genetics, metabolism, pathology)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasms, Experimental (genetics, metabolism, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Thioredoxin Reductase 1 (genetics, metabolism)