Distinct Roles for the Thioredoxin and Glutathione Antioxidant Systems in Nrf2-Mediated Lung Tumor Initiation and Progression

Abstract

AbstractRedox regulators are emerging as critical mediators of lung tumorigenesis. NRF2 and its negative regulator KEAP1 are commonly mutated in human lung cancers, leading to NRF2 accumulation and constitutive expression of NRF2 target genes, many of which are at the interface between antioxidant function and anabolic processes that support cellular proliferation. Nrf2 activation promotes lung tumor initiation and early progression in murine models of lung cancer, but which Nrf2 targets mediate these phenotypes is unknown. Nrf2 regulates two parallel antioxidant systems mediated by thioredoxin reductase 1 (TXNRD1) and glutathione reductase (GSR), which promote the reduction of protein antioxidant thioredoxin (TXN) and tripeptide antioxidant glutathione (GSH), respectively. We deleted TXNRD1 and GSR alone, or in combination, in lung tumors harboring mutations in KrasG12D and Nrf2D29H. We found that tumor initiation was promoted by expression of GSR, but not TXNRD1, regardless of Nrf2 status. In contrast, Nrf2D29H tumors, but not Nrf2WT, were dependent on TXNRD1 for tumor progression, while GSR was dispensable. Simultaneous deletion of GSR and TXNRD1 reduced initiation and progression independent of Nrf2 status, but surprisingly did not completely abrogate tumor formation. Thus, the thioredoxin and glutathione antioxidant systems play unique roles in tumor initiation and progression.