自噬
程序性细胞死亡
细胞生物学
细胞凋亡
细胞
细胞培养
细胞生长
坏死性下垂
癌细胞
ATG5型
作者
Yulin Zhang,Yang Kong,Yuan Ma,Shilei Ni,Tobias Espedal Wikerholmen,Kaiyan Xi,Feihu Zhao,Zhimin Zhao,Junpeng Wang,Bin Huang,Anjing Chen,Zhong Yao,Mingzhi Han,Zichao Feng,Yaotian Hu,Frits Thorsen,Jiang Wang,Xingang Li
出处
期刊:Oncogene
[Springer Nature]
日期:2021-01-08
卷期号:40 (8): 1425-1439
被引量:15
标识
DOI:10.1038/s41388-020-01622-3
摘要
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.
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