Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
Department of Neurological Surgery, Columbia University Medical Center, New York, NY 10032, USA.
Mol Cell. 2022 Aug 18;82(16):3061-3076.e6. doi: 10.1016/j.molcel.2022.06.030. Epub 2022 Aug 9.
Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM.
乳酸在胶质母细胞瘤（GBM）中大量积累，GBM 是最常见的原发性恶性脑肿瘤，预后不良。然而，目前尚不清楚乳酸是否由 GBM 代谢。在这里，我们证明了乳酸可以挽救患者来源的异种移植（PDX）GBM 细胞免受营养剥夺介导的细胞死亡。转录组分析、ATAC-seq 和 ChIP-seq 表明，乳酸具有氧化能量代谢的特征。LC/MS 分析表明，U-C-乳酸在 GBM 细胞中引起 TCA 循环代谢物、乙酰辅酶 A 和组蛋白乙酰残基的大量标记。乳酸以依赖于氧化能量代谢和 ATP-柠檬酸裂解酶（ACLY）的方式增强染色质可及性和组蛋白乙酰化。利用 GBM 的原位 PDX 模型，一项联合示踪实验表明，乳酸碳大量标记 TCA 循环代谢物。最后，在两种小鼠原位 PDX 模型中，氧化能量代谢的药理学阻断延长了整体存活时间。这些结果确立了乳酸代谢作为 GBM 的一种新的可药物化途径。
