Acyl-CoA-Binding Protein Drives Glioblastoma Tumorigenesis by Sustaining Fatty Acid Oxidation
Acyl-CoA-Binding Protein Drives Glioblastoma Tumorigenesis by Sustaining Fatty Acid Oxidation
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DOI：
10.1016/j.cmet.2019.04.004
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发表时间：
2019-08-06
期刊：
影响因子：
29
通讯作者：
Alfonso, Julieta
中科院分区：
文献类型：
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作者：
Duman, Ceren;Yaqubi, Kaneschka;Alfonso, Julieta
多形性胶质母细胞瘤（GBM）经历代谢重编程以满足肿瘤细胞的高ATP和合成代谢需求。然而，脂肪酸氧化（FAO）及其调节剂在GBM背景下的作用在很大程度上是未知的。在这里，我们发现神经干细胞促增殖因子酰基辅酶A结合蛋白（ACBP，也称为DBI）在GBM中高度表达，通过与酰基辅酶A结合，它在几种临床前模型中自主维持高增殖率，促进肿瘤生长和生存率低下。使用ACBP-酰基-CoA结合亲和力变体和药理学FAO调节剂的机制实验表明，ACBP通过控制线粒体的长链脂肪酰基-CoA的可用性来支持肿瘤生长，促进GBM中的FAO。因此，我们的研究结果揭示了ACBP建立的脂质代谢和GBM进展之间的关键联系，并为GBM的有效抗增殖代谢管理提供了潜在的治疗策略。
Glioblastoma multiforme (GBM) undergoes metabolic reprogramming to meet the high ATP and anabolic demands of the tumor cells. However, the role of fatty acid oxidation (FAO) and its regulators in the GBM context has been largely unknown. Here, we show that the neural stem cell pro-proliferative factor acyl-CoA-binding protein (ACBP, also known as DBI) is highly expressed in GBM, and by binding to acyl-CoAs, it cell-autonomously maintains high proliferation rates, promoting tumor growth and poor survival in several preclinical models. Mechanistic experiments using ACBP-acyl-CoA binding affinity variants and pharmacological FAO modulators suggest that ACBP supports tumor growth by controlling the availability of long-chain fatty acyl-CoAs to mitochondria, promoting FAO in GBM. Thus, our findings uncover a critical link between lipid metabolism and GBM progression established by ACBP and offer a potential therapeutic strategy for an effective anti-proliferative metabolic management of GBM.