Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress
Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress
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DOI：
10.1016/j.cmet.2020.06.002
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发表时间：
2020-08-04
期刊：
影响因子：
29
通讯作者：
Guo, Deliang
中科院分区：
文献类型：
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作者：
Cheng, Xiang;Geng, Feng;Guo, Deliang
胶质母细胞瘤（GBM）是一种致命的脑肿瘤，它需要大量的游离脂肪酸（FAs）来促进细胞生长。但这种癌症是如何避免脂肪毒性的还不得而知。在这里，我们发现GBM上调二酰基甘油酰基转移酶1 (DGAT1)，将多余的FAs储存到甘油三酯和脂滴中。抑制DGAT1破坏脂质稳态，导致过多的FAs进入线粒体氧化，导致高水平活性氧（ROS）的产生、线粒体损伤、细胞色素c释放和细胞凋亡。添加n -乙酰半胱氨酸或抑制FA进入线粒体可减少ROS和DGAT1抑制引起的细胞死亡。在异种移植物模型中，我们发现靶向DGAT1可阻断脂滴形成，诱导肿瘤细胞凋亡，并显著抑制GBM生长。总之，我们的研究表明，DGAT1上调可以保护GBM免受氧化损伤，并通过促进多余FAs的储存来维持脂质稳态。靶向DGAT1可能是治疗GBM的有希望的方法。
Glioblastoma (GBM), a mostly lethal brain tumor, acquires large amounts of free fatty acids (FAs) to promote cell growth. But how the cancer avoids lipotoxicity is unknown. Here, we identify that GBM upregulates diacylglycerol-acyltransferase 1 (DGAT1) to store excess FAs into triglycerides and lipid droplets. Inhibiting DGAT1 disrupted lipid homeostasis and resulted in excessive FAs moving into mitochondria for oxidation, leading to the generation of high levels of reactive oxygen species (ROS), mitochondrial damage, cytochrome c release, and apoptosis. Adding N-acetyl-cysteine or inhibiting FA shuttling into mitochondria decreased ROS and cell death induced by DGAT1 inhibition. Weshow in xenograft models that targeting DGAT1 blocked lipid droplet formation, induced tumor cell apoptosis, and markedly suppressed GBM growth. Together, our study demonstrates that DGAT1 upregulation protects GBM from oxidative damage and maintains lipid homeostasis by facilitating storage of excess FAs. Targeting DGAT1 could be a promising therapeutic approach for GBM.