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

细胞质和线粒体中的硫氧还蛋白减少：Trx1KO x Trx2KO 小鼠中与年龄相关的癌症发展的关键调节剂？

• 批准号: 10097763
• 负责人: YUJI IKENO
• 金额: $ 38.76万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10097763
• 关键词: Aging; Animals; Antioxidants; Apoptosis; Attenuated; Autophagocytosis; C57BL/6 Mouse; Cells; Cysteine; Cytosol; DNA; Development; Disease; Down-Regulation; Elderly; Environment; Excision; Female; Frequencies; Gene Expression; Genomic Instability; Goals; Growth; Health; Incidence; Intervention; Knockout Mice; LacZ Genes; Lead; Lipids; Longevity; Malignant Neoplasms; Mitochondria; Mole Rats; Molecular; Mus; Mutation; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathway interactions; Pharmacology; Physiological; Play; Population; Prevention therapy; Proteins; Reactive Oxygen Species; Reporting; Research; Risk; Role; Seminal; Severities; Signal Pathway; Signal Transduction; Superoxide Dismutase; TXN gene; Testing; Tissues; Wild Type Mouse; age related; anti-cancer; antioxidant enzyme; cancer prevention; cell injury; healthspan; improved; lipidomics; male; mouse model; novel; overexpression; oxidative damage; protein function; tumor

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.

这一提议是由于我们观察到硫氧还蛋白（Trx）在两种细胞中的下调而提出的。 小鼠体内的细胞质和线粒体 (Trx1KO x Trx2KO) 导致自发肿瘤形成减少 衰老和寿命略有延长。由于我们之前对 Trx1KO 或 Trx2KO 小鼠的研究表明 与野生型（WT）同窝小鼠相比，单独下调 Trx1 或 Trx2 会增强氧化应激， 细胞质和线粒体中 Trx 下调对年龄相关的有益影响 自发性肿瘤的形成是出乎意料的。为了进一步支持我们在 Trx1KO x Trx2KO 小鼠中的观察， 我们最近的报告表明，Trx 在细胞质和线粒体中联合过度表达 （Trx1Tg x Trx2Tg）在雄性 C57BL/6 小鼠中显着增强了癌症的发展，增加了其他 与 WT 同窝小鼠相比，它们的寿命显着缩短 (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，下调 细胞质和线粒体中的 Trx 通过以下方式减弱衰老过程中自发性癌症的发展 Trx 功能特有的机制。 Trx 是一种分子，具有以下作用： a) 在维持还原的细胞环境中发挥重要作用；和 b) 对于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，它是独特且极其重要的，因为 氧化还原敏感的信号通路对衰老的影响比氧化还原的积累更多样化 损害。与这一观点一致，Trx1KO x Trx2KO 小鼠肿瘤发展的减少与 具有多种信号传导/分子变化：a) 增强细胞凋亡途径； b) 增强自噬；和c) 与 WT 小鼠相比，对脂质的氧化损伤更少。这些观察结果表明，下调 细胞质和线粒体中的 Trx 通过以下方式抑制肿瘤发展：a) 增强去除 细胞凋亡受损； b) 通过自噬增强细胞损伤的清除。此举的目标 应用程序的目的是追求这些新发现并确定减少 Trx 的具体机制 细胞质和线粒体都能减弱衰老过程中癌症的发展。我们将测试以下内容 假设：细胞质和线粒体中 Trx 的下调会增强细胞凋亡 自噬，导致 DNA、蛋白质和脂质受损的受损细胞被清除， 这导致基因组不稳定性降低并抑制肿瘤发展。 这项研究将：a）显着扩展我们对氧化还原敏感作用的理解 信号通路在与年龄相关的癌症发展中发挥作用； b) 为与年龄相关的癌症提供重要线索 使用药物干预进行预防和治疗（例如硫氧还蛋白抑制）； c) 有影响 改善老年人的健康（特别是抗癌），从而延长他们的健康寿命。