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. Cancer Res; 70(22); 9505-14. ©2010 AACR.

Selective activation of oxidized PTP1B by the thioredoxin system modulates PDGF-β receptor tyrosine kinase signaling

“…1E), in agreement with previous findings showing compensatory up-regulation of the GSH system in TrxR1 null cells (45).…”

Selenoproteins: Molecular Pathways and Physiological Roles

“…First, TR1 may serve to prevent cancer by maintaining cellular redox homeostasis and decreasing the rate of mutations that initiate tumor formation. At the same time, TR1 is required for tumor growth due to high susceptibility of cancer cells to oxidative stress (98,243,303). In a recent study, the dual role of TR1 in cancer has been further investigated using conditional knockout of TR1 in liver in a chemically induced model of hepatocarcinogenesis (47).…”

DNA Replication in Animal Systems Lacking Thioredoxin Reductase I

“…As time passes, more and more cell types are being found to replicate in the absence of TrxR1. Recently, it was shown that lymphomas lacking TrxR1 can initiate and progress normally in mice (Mandal et al, 2010), adding another cell type to the list of cell types that can replicate in the absence of TrxR1. Also, in investigations using a fluorescent marker-tagged system in which both copies of the TrxR1 gene were disrupted in an arbitrary population of all cell types in fetal mice, my group assessed which, if any, cell types failed to contribute to the adult mouse two months later.…”

“…In each case, the homozygous-mutant zygote proliferates to yield thousands of TrxR1-deficient cells prior to embryonic failure. Subsequently, using regulated disruption of these conditional alleles, mouse cells homozygous null for either allele have been shown to replicate vigorously (Mandal et al, 2010;Rollins et al, 2010), suggesting proliferation is normal in TrxR1-deficient cells. Why, then, do the mutant embryos die?…”

“…Some recent advances have come from the development of mouse models bearing targeted "conditional" alleles of the gene encoding thioredoxin reductase I (TrxR1, also called Txnrd1 or TR1), which can be disrupted in a cell type-or developmental stage-specific manner. Whereas these models are yielding some exciting insights into the Trx and GSH systems in embryonic development, stress responses, toxicology, cancer, and other processes (Bondareva et al, 2007;Branco et al, 2011;Carvalho et al, 2008;Jakupoglu et al, 2005;Mandal et al, 2010;Rogers et al, 2004;Suvorova et al, 2009;Tipple et al, 2007;Zhang and Lu, 2007), the current treatise will emphasize the interplay of these pathways in supporting DNA replication in animal systems. The enormity of the body of literature on the Trx, GSH, and RNR systems precludes an exhaustive review of these materials, and it is my intention to cover these subjects in only a cursory manner to set the backdrop for understanding these systems in the context of DNA replication in animals.…”