One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Kimia Ghannad-Zadeh, Alyona Ivanova, Megan Wu, Taylor M Wilson, Alyssa Lau, Robert Flick, David G Munoz, Sunit Das
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Abstract

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.

单碳介导的嘌呤合成是胶质母细胞瘤产生替莫唑胺耐药性的原因。
胶质母细胞瘤占成人原发性恶性脑肿瘤的近一半,尽管采取了积极的治疗标准,包括切除手术和辅助化疗,但复发仍是普遍现象,总体中位生存期仅为 14.6 个月。最近的研究揭示了客体突变作为代谢适应关键介质在癌症进展中的重要性。在之前的研究中,我们发现了表观遗传修饰因子 ID-1 在胶质母细胞瘤的替莫唑胺耐药性中的作用。在这里,我们发现 ID-1 介导的胶质母细胞瘤肿瘤发生伴随着一碳(1-C)介导的嘌呤从头合成的上调。ID-1 基因敲除会导致一碳代谢和嘌呤合成酶的表达显著减少。对初次发病和复发时的胶质母细胞瘤手术标本进行分析后发现,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缩短相关。此外,我们还发现 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。补充外源性嘌呤可恢复 ID-1 缺乏细胞的增殖能力,而用 AICAR 抑制嘌呤合成可使对替莫唑胺耐药的胶质母细胞瘤细胞对替莫唑胺化疗敏感。我们的数据表明,在耐药胶质瘤细胞中观察到的代谢表型是胶质母细胞瘤的潜在治疗靶点。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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