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Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.

ABSTRACT: 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. We show 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.

SUBMITTER: Cheng X

PROVIDER: S-EPMC7415721 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.

Cheng Xiang X Geng Feng F Pan Meixia M Wu Xiaoning X Zhong Yaogang Y Wang Chunyan C Tian Zhihua Z Cheng Chunming C Zhang Rui R Puduvalli Vinay V Horbinski Craig C Mo Xiaokui X Han Xianlin X Chakravarti Arnab A Guo Deliang D

Cell metabolism 20200618 2

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) ...[more]

PMID: 32559414

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Dataset Information

Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.

Publications

Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.

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