Reduced thioredoxin in both the cytosol and mitochondria: a key modulator of age-related cancer development in Trx1KO x Trx2KO mice?

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This proposal is prompted by our observation that the down-regulation of thioredoxin (Trx) in both the cytosol and mitochondria (Trx1KO x Trx2KO) in mice resulted in reduced spontaneous tumor formation during aging and a slight extension of lifespan. Since our previous studies with Trx1KO or Trx2KO mice showed that the down-regulation of Trx1 or Trx2 alone enhanced oxidative stress compared to wild-type (WT) littermates, the beneficial effects of the down-regulation of Trx in both the cytosol and mitochondria on age-related spontaneous tumor formation were unanticipated. To further support our observation in Trx1KO x Trx2KO mice, our recent report demonstrated that the combined overexpression of Trx in both the cytosol and mitochondria (Trx1Tg x Trx2Tg) in male C57BL/6 mice had significantly enhanced cancer development, increased other diseases, and had a significantly shorter (16.3%) lifespan compared to their WT littermates. Therefore, our studies with Trx1KO x Trx2KO and Trx1Tg x Trx2Tg mice convincingly demonstrated that the down-regulation of Trx in both the cytosol and mitochondria attenuates spontaneous cancer development during aging through mechanisms specific to Trx function. Trx is a molecule that plays: a) an essential role in maintaining a reduced cellular environment; and b) critical roles for the normal function of proteins that contain cysteine residues. These physiological roles of Trx are unique and extremely important compared to other antioxidant enzymes because changes in the redox-sensitive signaling pathways have more diverse effects on aging than the accumulation of oxidative damage. Consistent with this notion, the reduced tumor development in Trx1KO x Trx2KO mice was associated with several signaling/molecular changes: a) enhanced apoptosis pathways; b) enhanced autophagy; and c) less oxidative damage to lipids compared to WT mice. These observations indicate that the down-regulation of Trx in both the cytosol and mitochondria results in suppressed tumor development by: a) enhanced removal of damaged cells by apoptosis; and b) enhanced removal of cellular damage by autophagy. The goal of this application is to pursue these novel findings and determine the specific mechanisms by which reduced Trx in both the cytosol and mitochondria attenuates cancer development during aging. We will test the following hypothesis: Trx down-regulation in both the cytosol and mitochondria enhances apoptosis and autophagy, resulting in the removal of damaged cells that have damage to DNA, proteins, and lipids, which leads to reduced genomic instability and suppressed tumor development. This research will: a) significantly expand our understanding about the roles that redox-sensitive signaling pathways play in age-related cancer development; b) provide important clues for age-related cancer prevention and therapy using pharmacological interventions (e.g., thioredoxin inhibition); and c) have an impact on improving the health of the elderly (specifically against cancer) resulting in an extension of their healthspan.