磷酸戊糖途径
未折叠蛋白反应
癌症研究
生物
细胞凋亡
代谢途径
RNA干扰
细胞生长
糖酵解
酶
核糖核酸
生物化学
基因
作者
Zhiyuan Zhu,Karrie Mei-Yee Kiang,Ning Li,Jiaxin Liu,Pingde Zhang,Lei Jin,Xiaozheng He,Shizhong Zhang,Gkk Leung
出处
期刊:Cancer Letters
[Elsevier BV]
日期:2022-09-08
卷期号:549: 215903-215903
被引量:14
标识
DOI:10.1016/j.canlet.2022.215903
摘要
The mitochondrial folate enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) has shown oncogenic roles in various cancers and may have non-metabolic functions. This study investigated the role of MTHFD2 in glioblastoma pathogenesis. We find that MTHFD2 expression is enriched in gliomas by analysing public databases and clinical specimens. RNA interference (RNAi) and inhibitor of MTHFD2 hamper the proliferation of glioblastoma and induce apoptosis in cell lines, glioma stem-like cells (GSCs) and patient-derived xenografts (PDX). Metabolomic analyses show that MTHFD2 depletion suppresses the central carbon metabolic pathways, including glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid (TCA) cycle. GSEA reveals a novel non-metabolic function of MTHFD2 in association with the unfolded protein response (UPR). MTHFD2 depletion activates the PERK/eIF2α axis which contributes to translation inhibition and apoptosis; these effects are attenuated by a PERK inhibitor. Mechanistically, MTHFD2 may be linked to UPR via the post-transcriptionally regulation of chaperone protein GRP78. In conclusion, MTHFD2 could be a promising therapeutic target for glioblastoma. Besides its canonical role, MTHFD2 may contribute to glioblastoma pathogenesis via UPR, highlighting a newly identified functional link between one-carbon metabolism and cell stress response.
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