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: 10681359
• 负责人: YUJI IKENO
• 金额: $ 42.59万
• 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/10681359
• 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; Lipids; Longevity; Malignant Neoplasms; Mitochondria; Mole Rats; Molecular; Mus; Mutation; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathway interactions; Physiological; Play; Population; 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; cancer therapy; cell injury; healthspan; improved; lipidomics; male; mouse model; novel; overexpression; oxidative damage; pharmacologic; 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.

这一建议是由我们观察到的硫氧还蛋白（Trx）在两个组织中的下调引起的。 细胞质和线粒体（Trx 1 KO × Trx 2KO）在小鼠中导致减少的自发性肿瘤形成， 老化和寿命的轻微延长。由于我们之前对Trx 1 KO或Trx 2 KO小鼠的研究表明， 单独下调Trx 1或Trx 2与野生型（WT）同窝仔相比增强了氧化应激， 细胞质和线粒体中Trx的下调对年龄相关的 自发肿瘤形成是意料之外的。为了进一步支持我们在Trx 1 KO x Trx 2KO小鼠中的观察， 我们最近的报道表明，Trx在细胞质和线粒体中的联合过表达， （Trx 1 Tg x Trx 2 Tg）在雄性C57 BL/6小鼠中显著增强了癌症发展，增加了其他 疾病，并且与它们的WT同窝仔相比具有显著更短的寿命（16.3%）。所以我们的 对Trx 1 KO × Trx 2KO和Trx 1 Tg × Trx 2 Tg小鼠的研究令人信服地证明， Trx在细胞质和线粒体中的表达减弱了衰老过程中自发性癌症的发展， Trx功能的特定机制。 Trx是一种分子，其发挥：a）在维持还原的细胞环境中起重要作用;和B） 对含有半胱氨酸残基的蛋白质的正常功能起关键作用。Trx的这些生理作用 与其他抗氧化酶相比是独特的，也是非常重要的，因为 氧化还原敏感的信号传导途径对衰老的影响比氧化应激的积累更多样化。 损害与这一观点一致，Trx 1 KO x Trx 2KO小鼠中肿瘤发展的减少与 具有几种信号传导/分子变化：a）增强的凋亡途径; B）增强的自噬;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， 细胞质和线粒体中的Trx通过以下方式导致抑制肿瘤发展：a）增强的对肿瘤的清除， 通过凋亡损伤的细胞;和B）通过自噬增强细胞损伤的去除。这个目标 应用是追求这些新的发现，并确定减少Trx的具体机制， 细胞质和线粒体都减弱了衰老过程中的癌症发展。我们将测试以下内容 假设：Trx在细胞质和线粒体中的下调增强了细胞凋亡， 自噬，导致去除对DNA、蛋白质和脂质有损伤的受损细胞， 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）显著扩大我们对氧化还原敏感的作用的理解， 信号通路在与年龄相关的癌症发展中起作用; B）为与年龄相关的癌症提供重要线索 使用药物干预的预防和治疗（例如，硫氧还蛋白抑制）;和c）具有影响 改善老年人的健康（特别是预防癌症），从而延长他们的健康寿命。

项目成果

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• DOI: 10.1007/s40122-022-00389-7
• 发表时间: 2022-06
• 期刊: PAIN AND THERAPY
• 影响因子: 4
• 作者: Chen, Shibiao;Wei, Aiping;Min, Jia;Li, Lei;Zhang, Yang
• 通讯作者: Zhang, Yang

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• DOI: 10.1007/s40122-022-00403-y
• 发表时间: 2022-09
• 期刊: PAIN AND THERAPY
• 影响因子: 4
• 作者: Zhang, Yang;Min, Jia;Chen, Shibiao
• 通讯作者: Chen, Shibiao