College of Life Science, Yangtze University, Jingzhou, 434025, China.
Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, 613 00, Czech Republic.
Arch Toxicol. 2023 Aug;97(8):2089-2109. doi: 10.1007/s00204-023-03540-1. Epub 2023 Jun 19.
Cellular senescence leads to decreased tissue regeneration and inflammation and is associated with diabetes, neurodegenerative diseases, and tumorigenesis. However, the mechanisms of cellular senescence are not fully understood. Emerging evidence has indicated that c-Jun N-terminal kinase (JNK) signaling is involved in the regulation of cellular senescence. JNK can downregulate hypoxia inducible factor-1α to accelerate hypoxia-induced neuronal cell senescence. The activation of JNK inhibits mTOR activity and triggers autophagy, which promotes cellular senescence. JNK can upregulate the expression of p53 and Bcl-2 and accelerates cancer cell senescence; however, this signaling also mediates the expression of amphiregulin and PD-LI to achieve cancer cell immune evasion and prevents their senescence. The activation of JNK further triggers forkhead box O expression and its target gene Jafrac1 to extend the lifespan of Drosophila. JNK can also upregulate the expression of DNA repair protein poly ADP-ribose polymerase 1 and heat shock protein to delay cellular senescence. This review discusses recent advances in understanding the function of JNK signaling in cellular senescence and includes a comprehensive analysis of the molecular mechanisms underlying JNK-mediated senescence evasion and oncogene-induced cellular senescence. We also summarize the research progress in anti-aging agents that target JNK signaling. This study will contribute to a better understanding of the molecular targets of cellular senescence and provides insights into anti-aging, which may be used to develop drugs for the treatment of aging-related diseases.
细胞衰老会导致组织再生和炎症减少，与糖尿病、神经退行性疾病和肿瘤发生有关。然而，细胞衰老的机制尚未完全阐明。新出现的证据表明，c-Jun N 端激酶（JNK）信号参与了细胞衰老的调节。JNK 可以下调缺氧诱导因子-1α，加速缺氧诱导的神经元细胞衰老。JNK 的激活抑制 mTOR 活性并引发自噬，从而促进细胞衰老。JNK 可以上调 p53 和 Bcl-2 的表达，加速癌细胞衰老；然而，这种信号还介导 Amphiregulin 和 PD-LI 的表达，以实现癌细胞的免疫逃逸，防止其衰老。JNK 的激活进一步触发叉头框 O 的表达及其靶基因 Jafrac1，以延长果蝇的寿命。JNK 还可以上调 DNA 修复蛋白聚 ADP-核糖聚合酶 1 和热休克蛋白的表达，以延缓细胞衰老。本综述讨论了 JNK 信号在细胞衰老中的功能的最新进展，包括对 JNK 介导的衰老逃逸和癌基因诱导的细胞衰老的分子机制的全面分析。我们还总结了针对 JNK 信号的抗衰老剂的研究进展。这项研究将有助于更好地理解细胞衰老的分子靶点，并为抗衰老提供思路，这可能用于开发治疗与衰老相关疾病的药物。
