Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; College of pharmacy, Changsha Medical University, Changsha 410219, China.
Biochim Biophys Acta Gen Subj. 2024 Nov;1868(11):130706. doi: 10.1016/j.bbagen.2024.130706. Epub 2024 Aug 23.
Ferroptosis, a type of autophagy-dependent cell death, has been implicated in the pathogenesis of lung adenocarcinoma (LUAD). This study aimed to investigate the involvement of coatomer protein complex I subunit zeta 1 (COPZ1) in ferroptosis and ferritinophagy in LUAD.
Publicly available human LUAD sample data were obtained from the TCGA database to analyze the association of COPZ1 expression with LUAD grade and patient survival. Clinical samples of LUAD and para-carcinoma tissues were collected. COPZ1-deficient LUAD cell model and xenograft model were established. These models were analyzed to evaluate tumor growth, lipid peroxidation levels, mitochondrial structure, autophagy activation, and iron metabolism.
High expression of COPZ1 was indicative of malignancy and poor overall survival. Clinical LUAD tissues showed increased COPZ1 expression and decreased nuclear receptor coactivator 4 (NCOA4) expression. COPZ1 knockdown inhibited xenograft tumor growth and induced apoptosis. COPZ1 knockdown elevated the levels of ROS, Fe and lipid peroxidation. COPZ1 knockdown also caused mitochondrial shrinkage. Liproxstatin-1, deferoxamine, and z-VAD-FMK reversed the effects of COPZ1 knockdown on LUAD cell proliferation and ferroptosis. Furthermore, COPZ1 was directly bound to NCOA4. COPZ1 knockdown restricted FTH1 expression and promoted NCOA4 and LC3 expression. NCOA4 knockdown reversed the regulation of iron metabolism, lipid peroxidation, and mitochondrial structure induced by COPZ1 knockdown. COPZ1 knockdown induced the translocation of ferritin to lysosomes for degradation, whereas NCOA4 knockdown disrupted this process.
This study provides novel evidence that COPZ1 regulates NCOA4-mediated ferritinophagy and ferroptosis. These findings provide new insights into the pathogenesis and potential treatment of LUAD.
铁死亡是一种自噬依赖性细胞死亡方式，与肺腺癌（LUAD）的发病机制有关。本研究旨在探讨衣被蛋白复合体 I 亚基 ζ1（COPZ1）在 LUAD 中铁死亡和铁蛋白自噬中的作用。
从 TCGA 数据库中获取公共的人 LUAD 样本数据，分析 COPZ1 表达与 LUAD 分级和患者生存的关系。收集 LUAD 和癌旁组织的临床样本。建立 COPZ1 缺陷的 LUAD 细胞模型和异种移植模型。分析这些模型以评估肿瘤生长、脂质过氧化水平、线粒体结构、自噬激活和铁代谢。
COPZ1 高表达提示恶性程度高，总生存期差。临床 LUAD 组织显示 COPZ1 表达增加，核受体共激活因子 4（NCOA4）表达降低。COPZ1 敲低抑制异种移植肿瘤生长并诱导细胞凋亡。COPZ1 敲低增加 ROS、Fe 和脂质过氧化水平。COPZ1 敲低还导致线粒体收缩。洛索司他汀-1、去铁胺和 z-VAD-FMK 逆转了 COPZ1 敲低对 LUAD 细胞增殖和铁死亡的影响。此外，COPZ1 直接与 NCOA4 结合。COPZ1 敲低限制 FTH1 表达并促进 NCOA4 和 LC3 表达。NCOA4 敲低逆转了 COPZ1 敲低诱导的铁代谢、脂质过氧化和线粒体结构的调节。COPZ1 敲低诱导铁蛋白向溶酶体的转位降解，而 NCOA4 敲低破坏了这一过程。
本研究提供了新的证据，证明 COPZ1 调节 NCOA4 介导的铁蛋白自噬和铁死亡。这些发现为 LUAD 的发病机制和潜在治疗提供了新的见解。
