Molecular targets of spermidine: implications for cancer suppression.

IF 4.1 Q2 CELL BIOLOGY
Andreas Zimmermann, Sebastian J Hofer, Frank Madeo
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Abstract

Spermidine is a ubiquitous, natural polyamine with geroprotective features. Supplementation of spermidine extends the lifespan of yeast, worms, flies, and mice, and dietary spermidine intake correlates with reduced human mortality. However, the crucial role of polyamines in cell proliferation has also implicated polyamine metabolism in neoplastic diseases, such as cancer. While depleting intracellular polyamine biosynthesis halts tumor growth in mouse models, lifelong external spermidine administration in mice does not increase cancer incidence. In contrast, a series of recent findings points to anti-neoplastic properties of spermidine administration in the context of immunotherapy. Various molecular mechanisms for the anti-aging and anti-cancer properties have been proposed, including the promotion of autophagy, enhanced translational control, and augmented mitochondrial function. For instance, spermidine allosterically activates mitochondrial trifunctional protein (MTP), a bipartite protein complex that mediates three of the four steps of mitochondrial fatty acid (β-oxidation. Through this action, spermidine supplementation is able to restore MTP-mediated mitochondrial respiratory capacity in naïve CD8+ T cells to juvenile levels and thereby improves T cell activation in aged mice. Here, we put this finding into the context of the previously described molecular target space of spermidine.

Abstract Image

亚精胺的分子靶点:对癌症抑制的影响。
亚精胺是一种普遍存在的天然多胺,具有保护老人的功能。补充亚精胺可延长酵母菌、蠕虫、苍蝇和小鼠的寿命,饮食中摄入亚精胺可降低人类死亡率。然而,多胺在细胞增殖中的关键作用也涉及肿瘤疾病(如癌症)中的多胺代谢。虽然在小鼠模型中,消耗细胞内多胺生物合成会阻止肿瘤生长,但小鼠终身外用亚精胺不会增加癌症发病率。相反,最近的一系列研究结果指出,在免疫治疗的背景下,亚精胺给药具有抗肿瘤特性。抗衰老和抗癌特性的各种分子机制已被提出,包括促进自噬,增强翻译控制和增强线粒体功能。例如,亚胺变构激活线粒体三功能蛋白(MTP),这是一种由两部分组成的蛋白质复合物,介导线粒体脂肪酸(β-氧化)的四个步骤中的三个步骤。通过这一作用,补充亚精胺能够将mtp介导的naïve CD8+ T细胞的线粒体呼吸能力恢复到幼年水平,从而改善老年小鼠的T细胞活化。在这里,我们把这一发现纳入之前描述的亚精胺分子靶空间的背景下。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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