Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines.
Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines.
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COPZ1的缺失诱导胶质母细胞瘤细胞系中NCOA 4介导的自噬和铁凋亡。
DOI：
10.1038/s41388-020-01622-3
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发表时间：
2021-03
期刊：
影响因子：
8
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Zhang Y;Kong Y;Ma Y;Ni S;Wikerholmen T;Xi K;Zhao F;Zhao Z;Wang J;Huang B;Chen A;Yao Z;Han M;Feng Z;Hu Y;Thorsen F;Wang J;Li X
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，我们鉴定了外被体蛋白复合物zeta 1亚基（COPZ 1）作为治疗靶点候选物，其显著失调GBM细胞中的铁代谢。基于对来自公开数据库癌症基因组图谱的表达数据的分析，COPZ 1的过表达与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，与非肿瘤性脑组织样品相比，GBM中COPZ 1的蛋白质水平显著增加。siRNA敲低COPZ 1抑制U87 MG、U251和P3#GBM的体外增殖。在U87 MG中稳定表达COPZ 1 shRNA构建体在植入后第21天相对于对照抑制了约60%的体内肿瘤生长（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（敲低，P < 0.05）。COPZ 1敲除还导致核受体辅激活因子4（NCOA 4）的增加，导致铁蛋白的降解，以及随后的细胞内亚铁水平的增加和最终的铁凋亡。这些数据表明COPZ 1是铁代谢中的关键介质。因此，COPZ 1/NCOA 4/FTH 1轴是用于治疗人GBM的新的治疗靶标。
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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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
64.8
作者：
Mancias, Joseph D.;Wang, Xiaoxu;Gygi, Steven P.;Harper, J. Wade;Kimmelman, Alec C.
通讯作者：
Kimmelman, Alec C.
影响因子：
15.9
作者：
Dolecek, Therese A.;Propp, Jennifer M.;Kruchko, Carol
通讯作者：
Kruchko, Carol
影响因子：
78.5
作者：
Mathew, Robin;Karantza-Wadsworth, Vassiliki;White, Eileen
通讯作者：
White, Eileen
人胶质母细胞瘤中 CYP46A1 缺失介导的胆固醇稳态改变的治疗意义
影响因子：
11.1
作者：
Han, Mingzhi;Wang, Shuai;Wang, Jian
通讯作者：
Wang, Jian