The Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, Toronto, ON, Canada.
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Cell Death Dis. 2024 Oct 25;15(10):774. doi: 10.1038/s41419-024-07170-y.
Glioblastoma accounts for nearly half of all primary malignant brain tumors in adults, and despite an aggressive standard of care, including excisional surgery and adjuvant chemoradiation, recurrence remains universal, with an overall median survival of 14.6 months. Recent work has revealed the importance of passenger mutations as critical mediators of metabolic adaptation in cancer progression. In our previous work, we identified a role for the epigenetic modifier ID-1 in temozolomide resistance in glioblastoma. Here, we show that ID-1-mediated glioblastoma tumourigenesis is accompanied by upregulation of one-carbon (1-C) mediated de novo purine synthesis. ID-1 knockout results in a significant reduction in the expression of 1-C metabolism and purine synthesis enzymes. Analysis of glioblastoma surgical specimens at initial presentation and recurrence reveals that 1-C purine synthesis metabolic enzymes are enriched in recurrent glioblastoma and that their expression correlates with a shorter time to tumor recurrence. Further, we show that the 1-C metabolic phenotype underlies proliferative capacity and temozolomide resistance in glioblastoma cells. Supplementation with exogenous purines restores proliferation in ID-1-deficient cells, while inhibition of purine synthesis with AICAR sensitizes temozolomide-resistant glioblastoma cells to temozolomide chemotherapy. Our data suggest that the metabolic phenotype observed in treatment-resistant glioma cells is a potential therapeutic target in glioblastoma.
胶质母细胞瘤占成人原发性恶性脑肿瘤的近一半，尽管采用了包括手术切除和辅助放化疗在内的积极标准治疗方法，但仍普遍复发，总体中位生存期为 14.6 个月。最近的研究揭示了乘客突变作为癌症进展中代谢适应的关键介质的重要性。在我们之前的工作中，我们确定了表观遗传修饰因子 ID-1 在替莫唑胺耐药性胶质母细胞瘤中的作用。在这里，我们表明 ID-1 介导的胶质母细胞瘤发生伴随着一碳（1-C）介导的从头嘌呤合成的上调。ID-1 敲除导致 1-C 代谢和嘌呤合成酶的表达显著减少。对初始表现和复发时的胶质母细胞瘤手术标本进行分析表明，1-C 嘌呤合成代谢酶在复发性胶质母细胞瘤中富集，其表达与肿瘤复发时间较短相关。此外，我们表明 1-C 代谢表型是胶质母细胞瘤细胞增殖能力和替莫唑胺耐药性的基础。外源性嘌呤的补充恢复了 ID-1 缺陷细胞的增殖能力，而用 AICAR 抑制嘌呤合成使替莫唑胺耐药性胶质母细胞瘤细胞对替莫唑胺化疗敏感。我们的数据表明，在治疗耐药性胶质细胞瘤细胞中观察到的代谢表型是胶质母细胞瘤的一个潜在治疗靶点。
