德克萨斯大学甘波谊研究组宣布他们的论文发现了放疗促进铜沉降并与铜死亡诱导剂协同克服肿瘤放射抗性。该项研究成果发表在2025年4月10日出版的《癌细胞》上。

研究小组发现放疗（RT）诱导癌细胞铜沉降，独立于细胞凋亡和铁沉降，并消耗患者肿瘤中脂酰化蛋白和铁硫（Fe-S）簇蛋白，这两种蛋白都是铜沉降的标志。在机制上，RT通过上调铜转运蛋白1 （copper transporter 1, CTR1）和消耗线粒体谷胱甘肽（一种铜螯合剂）来提高线粒体铜水平，从而引发铜还原。综合分析放射耐药食管癌细胞的RNA测序（RNA-seq）和放疗无反应食管癌患者的单细胞RNA测序（RNA-seq），发现放射耐药与BTB和CNC同源蛋白1 （BACH1）下调有关。这种下调抑制了铜螯合金属硫蛋白（MT） 1E/X的表达，从而减轻了铜增生并促进了辐射抗性。铜离子载体治疗通过增强铜增殖使放射耐药的癌细胞和细胞系及患者来源的异种移植物对放射治疗增敏。他们的发现揭示了放疗与铜死亡之间的联系，并为通过靶向铜死亡来克服肿瘤放射耐药的治疗策略提供了信息。

据悉，铜增生是最近发现的一种依赖铜的细胞死亡形式。

附：英文原文

Title: Radiotherapy promotes cuproptosis and synergizes with cuproptosis inducers to overcome tumor radioresistance

Author: Guang Lei, Mingchuang Sun, Jun Cheng, Rui Ye, Zhengze Lu, Amber Horbath, David Huo, Shengrong Wu, Anagha Alapati, Sadhna Aggarwal, Zhihao Xu, Chao Mao, Yuelong Yan, Jun Yao, Qidong Li, Xiong Chen, Hyemin Lee, Li Zhuang, Dadi Jiang, Apar Pataer, Jack A. Roth, Nicholas Navin, Albert C. Koong, Mingjian James You, Steven H. Lin, Boyi Gan

Issue&Volume: 2025-04-10

Abstract: Cuproptosis is a recently identified form of copper-dependent cell death. Here, we reveal that radiotherapy (RT) induces cuproptosis in cancer cells, independent of apoptosis and ferroptosis, and depletes lipoylated proteins and iron-sulfur (Fe-S) cluster proteins—both hallmarks of cuproptosis—in patient tumors. Mechanistically, RT elevates mitochondrial copper levels by upregulating copper transporter 1 (CTR1) and depleting mitochondrial glutathione, a copper chelator, thereby triggering cuproptosis. Integrated analyses of RNA sequencing (RNA-seq) from radioresistant esophageal cancer cells and single-cell RNA-seq from esophageal tumors of patients unresponsive to RT link radioresistance to the downregulation of BTB and CNC homology 1 (BACH1). This downregulation de-represses the expression of copper-sequestering metallothionein (MT) 1E/X, thereby mitigating cuproptosis and contributing to radioresistance. Copper ionophore treatment sensitizes radioresistant cancer cells and cell line- and patient-derived xenografts to RT by potentiating cuproptosis. Our findings unveil a link between RT and cuproptosis and inform a therapeutic strategy to overcome tumor radioresistance by targeting cuproptosis.

DOI: 10.1016/j.ccell.2025.03.031

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00132-1