Fu Yuhan, Hou Lirui, Han Kai, Zhao Chong, Hu Hongbo, Yin Shutao
Department of Nutrition and Food Safety, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing 100083, China.
Cells. 2025 Mar 7;14(6):391. doi: 10.3390/cells14060391.
Cuproptosis is a form of copper-dependent non-apoptotic cell death. Cancer cells that prefer to use aerobic glycolysis for energy generation are commonly insensitive to cuproptosis, which hinders its application for cancer treatment. Epigallocatechin gallate (EGCG) possesses diverse pharmacological activities. However, the association between EGCG and cuproptosis has not been studied.
The cell viability, proliferation, and cuproptosis-related protein levels were detected to investigate whether EGCG enhances the sensitivity of HCC cells to cuproptosis. The intracellular copper level, related copper metabolism proteins, and gene expression were detected to explore the mechanisms. In addition, a nude mouse xenograft model was established to determine the effects of EGCG on cuproptosis in tumor tissues.
The combination of EGCG and copper ionophores significantly enhanced the mortality of HCC cells and heightened the sensitivity of HCC cells to cuproptosis. There was a notable reduction in the expression of copper export protein copper-transporting P-type ATPase (ATP7B). EGCG effectively suppressed metal regulatory transcription factor (MTF1) expression and subsequently hindered the transcriptional regulation of ATP7B. EGCG also facilitated the intratumoral accumulation of copper and augmented susceptibility to cuproptosis in vivo.
EGCG can increase the sensitivity of hepatocellular carcinoma cells to cuproptosis by promoting intracellular copper accumulation through the MTF1/ATP7B axis.
铜死亡是一种铜依赖性非凋亡性细胞死亡形式。倾向于利用有氧糖酵解产生能量的癌细胞通常对铜死亡不敏感，这阻碍了其在癌症治疗中的应用。表没食子儿没食子酸酯（EGCG）具有多种药理活性。然而，EGCG与铜死亡之间的关联尚未得到研究。
检测细胞活力、增殖以及与铜死亡相关的蛋白水平，以研究EGCG是否增强肝癌细胞对铜死亡的敏感性。检测细胞内铜水平、相关铜代谢蛋白和基因表达，以探索其机制。此外，建立裸鼠异种移植模型，以确定EGCG对肿瘤组织中铜死亡的影响。
EGCG与铜离子载体联合使用显著提高了肝癌细胞的死亡率，并增强了肝癌细胞对铜死亡的敏感性。铜输出蛋白铜转运P型ATP酶（ATP7B）的表达显著降低。EGCG有效抑制金属调节转录因子（MTF1）的表达，随后阻碍了ATP7B的转录调控。EGCG还促进了肿瘤内铜的积累，并增强了体内对铜死亡的易感性。
EGCG可通过MTF1/ATP7B轴促进细胞内铜积累，从而增加肝癌细胞对铜死亡的敏感性。
