COPZ1 缺失诱导胶质母细胞瘤细胞系中 NCOA4 介导的自噬和铁死亡,Oncogene

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COPZ1 缺失诱导胶质母细胞瘤细胞系中 NCOA4 介导的自噬和铁死亡
Oncogene ( IF 6.9 ) Pub Date : 2021-01-08 , DOI: 10.1038/s41388-020-01622-3
Yulin Zhang _{1,

2,

3} , Yang Kong _{1,

2,

3} , Yuan Ma _{1,

2} , Shilei Ni _{1,

2} , Tobias Wikerholmen ₃ , Kaiyan Xi _{1,

2} , Feihu Zhao _{1,

2} , Zhimin Zhao _{1,

2} , Junpeng Wang _{1,

2} , Bin Huang _{1,

2} , Anjing Chen _{1,

2} , Zhong Yao _{1,

2} , Mingzhi Han ₃ , Zichao Feng _{1,

2} , Yaotian Hu _{1,

2} , Frits Thorsen _{1,

3,

4} , Jian Wang _{1,

2,

3} , Xingang Li _{1,

2}

Affiliation

铁代谢失调是许多癌症的标志，包括胶质母细胞瘤 (GBM)。然而，其在肿瘤进展中的作用仍不清楚。在此，我们将 coatomer 蛋白复合物亚基 zeta 1 (COPZ1) 鉴定为治疗靶标候选物，它显着失调了 GBM 细胞中的铁代谢。基于对公开数据库 The Cancer Genome Atlas 的表达数据的分析， COPZ1的过表达与神经胶质瘤患者的肿瘤分级增加和预后不良相关（P < 0.001)。在免疫组织化学和蛋白质印迹分析中，与非肿瘤脑组织样本相比，GBM 中 COPZ1 的蛋白质水平显着增加。COPZ1 的 SiRNA 敲低在体外抑制了 U87MG、U251 和 P3#GBM 的增殖。在植入后第 21 天，相对于对照组，COPZ1 shRNA 构建体在 U87MG 中的稳定表达抑制体内肿瘤生长约 60%（P < 0.001）。生存数据的 Kaplan-Meier 分析表明，荷瘤动物的总生存期从 20.8 天（对照）增加到 27.8 天（击倒，P < 0.05)。COPZ1 敲低还导致核受体共激活因子 4 (NCOA4) 增加，导致铁蛋白降解，随后细胞内亚铁水平增加，最终导致铁死亡。这些数据表明 COPZ1 是铁代谢的关键介质。因此，COPZ1/NCOA4/FTH1 轴是治疗人类 GBM 的新型治疗靶点。

"点击查看英文标题和摘要"

Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines

Dysregulated iron metabolism is a hallmark of many cancers, including glioblastoma (GBM). However, its role in tumor progression remains unclear. Herein, we identified coatomer protein complex subunit zeta 1 (COPZ1) as a therapeutic target candidate which significantly dysregulated iron metabolism in GBM cells. Overexpression of COPZ1 was associated with increasing tumor grade and poor prognosis in glioma patients based on analysis of expression data from the publicly available database The Cancer Genome Atlas (P < 0.001). Protein levels of COPZ1 were significantly increased in GBM compared to non-neoplastic brain tissue samples in immunohistochemistry and western blot analysis. SiRNA knockdown of COPZ1 suppressed proliferation of U87MG, U251 and P3#GBM in vitro. Stable expression of a COPZ1 shRNA construct in U87MG inhibited tumor growth in vivo by ~60% relative to controls at day 21 after implantation (P < 0.001). Kaplan–Meier analysis of the survival data demonstrated that the overall survival of tumor bearing animals increased from 20.8 days (control) to 27.8 days (knockdown, P < 0.05). COPZ1 knockdown also led to the increase in nuclear receptor coactivator 4 (NCOA4), resulting in the degradation of ferritin, and a subsequent increase in the intracellular levels of ferrous iron and ultimately ferroptosis. These data demonstrate that COPZ1 is a critical mediator in iron metabolism. The COPZ1/NCOA4/FTH1 axis is therefore a novel therapeutic target for the treatment of human GBM.

更新日期：2021-01-08

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