Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cell Death Differ. 2023 Apr;30(4):876-884. doi: 10.1038/s41418-023-01125-0. Epub 2023 Feb 8.
Cuproptosis is a novel type of copper-induced cell death that primarily occurs in cells that utilize oxidative phosphorylation as the main metabolic pathway to produce energy. Copper directly associates with the lipoylated proteins of the tricarboxylic acid cycle, leading to the disulfide-bond-dependent aggregation of these lipoylated proteins, destabilization of the iron-sulfur cluster proteins, and consequent proteotoxic stress. Cancer cells prefer glycolysis (Warburg effect) to oxidative phosphorylation for producing intermediate metabolites and energy, thereby achieving resistance to cuproptosis. Interestingly, the tumor suppressor p53 is a crucial metabolic regulator that inhibits glycolysis and drives a metabolic switch towards oxidative phosphorylation in cancer cells. Additionally, p53 regulates the biogenesis of iron-sulfur clusters and the copper chelator glutathione, which are two critical components of the cuproptotic pathway, suggesting that this tumor suppressor might play a role in cuproptosis. Furthermore, the possible roles of mutant p53 in regulating cuproptosis are discussed. In this essay, we review the recent progress in the understanding of the mechanism underlying cuproptosis, revisit the roles of p53 in metabolic regulation and iron-sulfur cluster and glutathione biosynthesis, and propose several potential mechanisms for wild-type and mutant p53-mediated cuproptosis regulation.
铜死亡是一种新型的铜诱导细胞死亡，主要发生在利用氧化磷酸化作为主要代谢途径来产生能量的细胞中。铜直接与三羧酸循环的脂酰化蛋白结合，导致这些脂酰化蛋白的二硫键依赖性聚集，铁硫簇蛋白的不稳定性，以及随之而来的蛋白毒性应激。癌细胞更喜欢糖酵解（瓦博格效应）而不是氧化磷酸化来产生中间代谢物和能量，从而对铜死亡产生抵抗。有趣的是，肿瘤抑制因子 p53 是一种关键的代谢调节剂，它抑制糖酵解并促使癌细胞的代谢向氧化磷酸化转变。此外，p53 调节铁硫簇和铜螯合剂谷胱甘肽的生物发生，这是铜死亡途径的两个关键组成部分，表明这种肿瘤抑制因子可能在铜死亡中发挥作用。此外，还讨论了突变型 p53 在调节铜死亡中的可能作用。在本文中，我们回顾了对铜死亡机制理解的最新进展，重新审视了 p53 在代谢调节和铁硫簇及谷胱甘肽生物合成中的作用，并提出了野生型和突变型 p53 介导的铜死亡调节的几种潜在机制。
