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

这一建议是因为我们观察到硫氧还蛋白(Trx)在两种情况下的下调 小鼠胞浆和线粒体(Trx1KO X Trx2KO)导致自发性肿瘤形成减少 衰老，寿命略有延长。因为我们之前对Trx1KO或Trx2KO小鼠的研究表明 与野生型(WT)产仔相比，Trx1或Trx2的下调单独增强了氧化应激， 胞浆和线粒体中TRX的下调对年龄相关的有利影响 自发的肿瘤形成是意想不到的。为了进一步支持我们在Trx1KO x Trx2KO小鼠身上的观察， 我们最近的报告表明，Trx在细胞质和线粒体中的联合过表达 (Trx1Tg X Trx2Tg)在雄性C57BL/6小鼠中显著促进了肿瘤的发展，增加了其他 与它们产下的小鼠相比，它们的寿命显著缩短(16.3%)。因此，我们的 对Trx1KO x Trx2KO和Trx1Tg x Trx2Tg小鼠的研究令人信服地证明了下调 胞浆和线粒体中的Trx通过抑制衰老过程中的自发性癌症发展 特定于TRX功能的机制。 Trx是一种分子，它在维持减少的细胞环境中起着至关重要的作用； 对含有半胱氨酸残基的蛋白质的正常功能至关重要。Trx的这些生理作用 与其他抗氧化酶相比是独特的，也是极其重要的，因为 与氧化累积相比，氧化还原敏感的信号通路对衰老的影响更为多样 损坏。与这一概念一致的是，Trx1KO x Trx2KO小鼠肿瘤发展的减少与 有几个信号/分子变化：a)增强的凋亡途径；b)增强的自噬；以及c) 与WT小鼠相比，对血脂的氧化损伤更小。这些观察表明，下调对 胞浆和线粒体中的Trx通过以下方式抑制肿瘤的发展：a)增强对 通过细胞凋亡破坏细胞；以及b)通过自噬增强对细胞损害的清除。这样做的目的是 应用是追求这些新的发现，并确定减少TRX的具体机制 在衰老过程中，胞浆和线粒体都能延缓癌症的发展。我们将测试以下内容 假设：Trx在胞浆和线粒体中的下调促进了细胞的凋亡和 自噬，导致对DNA、蛋白质和脂类有损害的受损细胞被移除， 这会降低基因组的不稳定性，抑制肿瘤的发展。 这项研究将：a)显著扩展我们对氧化还原敏感的角色的理解 信号通路在年龄相关癌症的发展中发挥作用；b)为年龄相关癌症提供重要线索 使用药物干预措施(例如，硫氧还蛋白抑制)进行预防和治疗；以及c)产生影响 关于改善老年人的健康(特别是抗癌)，以延长他们的健康寿命。

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.