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

Authors
  • Cheng, Xiang1
  • Geng, Feng1
  • Pan, Meixia2
  • Wu, Xiaoning1
  • Zhong, Yaogang1
  • Wang, Chunyan2
  • Tian, Zhihua1
  • Cheng, Chunming1
  • Zhang, Rui1
  • Puduvalli, Vinay3
  • Horbinski, Craig4
  • Mo, Xiaokui5
  • Han, Xianlin6
  • Chakravarti, Arnab1
  • Guo, Deliang7
  • 1 Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine at The Ohio State University, Columbus, OH 43210, USA.
  • 2 Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 3 Division of Neuro-Oncology, Department of Neurology, The Ohio State University, Columbus, OH 43210, USA.
  • 4 Departments of Pathology and Neurosurgery, Feinberg School of Medicine at Northwestern University, Chicago, IL 60611, USA.
  • 5 Biostatistic Center and Department of Bioinformatics, College of Medicine at The Ohio State University, Columbus, OH 43210, USA.
  • 6 Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 7 Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cell metabolism
Publication Date
Aug 04, 2020
Volume
32
Issue
2
Identifiers
DOI: 10.1016/j.cmet.2020.06.002
PMID: 32559414
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2020 Elsevier Inc. All rights reserved.

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