MCT4 regulates de novo pyrimidine biosynthesis in GBM in a lactate-independent manner.
MCT4 regulates de novo pyrimidine biosynthesis in GBM in a lactate-independent manner.
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MCT4 以不依赖于乳酸的方式调节 GBM 中的从头嘧啶生物合成。
DOI：
10.1093/noajnl/vdz062
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Bar,EliE
中科院分区：
文献类型：
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作者：
Spina,Raffaella;Voss,DillonM;Yang,Xiaohua;Sohn,JasonW;Vinkler,Robert;Schraner,Julianna;Sloan,Anthony;Welford,ScottM;Avril,Norbert;Ames,HeatherM;Woodworth,GraemeF;Bar,EliE
背景胶质母细胞瘤（GBM）的组织学特征是坏死灶伴周围缺氧细胞假排列和微血管增生。我们以前已经表明，单羧酸转运蛋白4（MCT 4）是高表达的GBM的坏死/缺氧区域，并增加MCT 4的水平与更糟糕的临床outcomes.MethodsA相结合的转录组学和代谢组学分析进行研究MCT 4耗尽缺氧GBM神经球的影响。稳定和诱导的MCT 4耗尽系统被用来评估的影响和强调与MCT 4耗尽在体外和体内，单独和结合radiation.ResultsThis研究建立的机制，条件耗尽MCT 4深刻损害自我更新和减少的频率和致瘤性的侵略性，治疗耐药，胶质母细胞瘤干细胞。从机制上讲，我们观察到MCT 4缺失诱导回补性的氨基分解并消除从头嘧啶生物合成。后者导致DNA损伤和凋亡性细胞死亡的急剧增加，这些表型很容易通过补充嘧啶核苷来挽救。因此，我们发现，MCT 4消耗促进了建立原位异种移植动物的生存期的显着延长，这种效果延长了辅助治疗与focusedradiation.ConclusionsOur的研究结果建立了一个新的作用MCT 4作为一个关键的调节细胞脱氧核糖核苷酸水平，并提供了一个新的治疗方向MCT 4耗尽GBM。
BackgroundNecrotic foci with surrounding hypoxic cellular pseudopalisades and microvascular hyperplasia are histological features found in glioblastoma (GBM). We have previously shown that monocarboxylate transporter 4 (MCT4) is highly expressed in necrotic/hypoxic regions in GBM and that increased levels of MCT4 are associated with worse clinical outcomes.MethodsA combined transcriptomics and metabolomics analysis was performed to study the effects of MCT4 depletion in hypoxic GBM neurospheres. Stable and inducible MCT4-depletion systems were used to evaluate the effects of and underlining mechanisms associated with MCT4 depletion in vitro and in vivo, alone and in combination with radiation.ResultsThis study establishes that conditional depletion of MCT4 profoundly impairs self-renewal and reduces the frequency and tumorigenicity of aggressive, therapy-resistant, glioblastoma stem cells. Mechanistically, we observed that MCT4 depletion induces anaplerotic glutaminolysis and abrogates de novo pyrimidine biosynthesis. The latter results in a dramatic increase in DNA damage and apoptotic cell death, phenotypes that were readily rescued by pyrimidine nucleosides supplementation. Consequently, we found that MCT4 depletion promoted a significant prolongation of survival of animals bearing established orthotopic xenografts, an effect that was extended by adjuvant treatment with focused radiation.ConclusionsOur findings establish a novel role for MCT4 as a critical regulator of cellular deoxyribonucleotide levels and provide a new therapeutic direction related to MCT4 depletion in GBM.