Department of Functional Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangzhou, China; Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Cancer Lett. 2022 Nov 28;549:215903. doi: 10.1016/j.canlet.2022.215903. Epub 2022 Sep 8.
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.
线粒体叶酸酶亚甲基四氢叶酸脱氢酶/环水合酶（MTHFD2）在各种癌症中表现出致癌作用，并且可能具有非代谢功能。本研究探讨了 MTHFD2 在神经胶质瘤发病机制中的作用。我们通过分析公共数据库和临床标本发现，MTHFD2 在神经胶质瘤中表达丰富。RNA 干扰（RNAi）和 MTHFD2 抑制剂可抑制神经胶质瘤细胞系、神经胶质瘤干细胞样细胞（GSCs）和患者来源的异种移植物（PDX）的增殖并诱导细胞凋亡。代谢组学分析表明，MTHFD2 耗竭可抑制中央碳代谢途径，包括糖酵解、戊糖磷酸途径（PPP）和三羧酸（TCA）循环。GSEA 揭示了 MTHFD2 的一种新的非代谢功能，与未折叠蛋白反应（UPR）有关。MTHFD2 耗竭可激活 PERK/eIF2α 轴，导致翻译抑制和细胞凋亡；PERK 抑制剂可减弱这些作用。在机制上，MTHFD2 可能通过伴侣蛋白 GRP78 的转录后调节与 UPR 相关。总之，MTHFD2 可能是神经胶质瘤有前途的治疗靶点。除了其典型作用外，MTHFD2 还可能通过 UPR 促进神经胶质瘤的发病机制，突出了一碳代谢与细胞应激反应之间新发现的功能联系。
