@article{a4a34644ff594ef68dde979df44f13d0,
title = "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.",
keywords = "DGAT1, ROS, acylcarnitine, fatty acids, glioblastoma, lipid droplets, lipotoxicity, mitochondria, oxidative stress, triglycerides",
author = "Xiang Cheng and Feng Geng and Meixia Pan and Xiaoning Wu and Yaogang Zhong and Chunyan Wang and Zhihua Tian and Chunming Cheng and Rui Zhang and Vinay Puduvalli and Craig Horbinski and Xiaokui Mo and Xianlin Han and Arnab Chakravarti and Deliang Guo",
note = "Funding Information: This work was supported by National Institute of Neurological Disorders and Stroke ( NINDS ) and National Cancer Institute ( NCI ) of United States grants R01NS104332 , R01NS112935 , and R01CA240726 to D.G.; R01CA227874 to D.G. and A.C.; and American Cancer Society (United States) Research Scholar grant RSG-14-228-01–CSM to D.G. We also appreciate the support from OSUCCC -Pelotonia (United States) Idea grant and start-up funds to D.G. We thank Dr. Martine Torres for her critical review and helpful comments of the manuscript. Funding Information: Over the past two decades, the prognosis for GBM has remained very dismal, with an average survival of only 12?15 months, despite aggressive treatment (Wen and Reardon, 2016). One of the main reasons for this limited progress is a lack of full understanding of GBM biology. We previously uncovered that de novo FA synthesis is greatly increased in GBM to support its rapid growth ( Cheng et al., 2015; Geng et al., 2016; Guo, 2016; Guo et al., 2009a, 2009b, 2011, 2013, 2014; Ru and Guo, 2017; Ru et al., 2016). We recently further identified that increased glucose in cancer cells activates sterol regulatory element-binding protein-1 (SREBP-1), a master transcriptional factor that controls de novo fatty acid synthesis ( Cheng et al., 2018a, 2018b), promoting the conversion of excess glucose into fatty acids ( Cheng et al., 2015; Guo, 2016). It seems counterintuitive for cancer cells to keep synthesizing new FAs while storing large amounts of them into TGs and LDs. Nevertheless, we believe that synthesizing and storing excess FAs under rich nutrient conditions is a greatly advantageous means developed by malignant tumors. In the tumor microenvironment, nutrient levels are always fluctuating (Muir and Vander Heiden, 2018). When nutrient levels decrease, tumor cells could quickly utilize LDs to release free FAs for structural lipid synthesis and for energy production via elevation of FA oxidation, facilitating tumor cell survival under harsh conditions. This mechanism has the advantage to quickly boost malignant tumor growth. This concept is strongly supported by several recent studies that demonstrated that FA oxidation is important for GBM growth, showing that inhibition of FA oxidation significantly suppressed GBM growth ( Duman et al., 2019; Lin et al., 2017). Nevertheless, even under low-nutrient conditions such as glucose reduction, the homeostasis of FA metabolism needs to be maintained. Our data strongly suggest that although FA oxidation rate varies in the tumor microenvironment, overflow of FAs to mitochondria for oxidation remains very toxic for tumor cells, even under low-glucose conditions.This work was supported by National Institute of Neurological Disorders and Stroke (NINDS) and National Cancer Institute (NCI) of United States grants R01NS104332, R01NS112935, and R01CA240726 to D.G.; R01CA227874 to D.G. and A.C.; and American Cancer Society (United States) Research Scholar grant RSG-14-228-01?CSM to D.G. We also appreciate the support from OSUCCC-Pelotonia (United States) Idea grant and start-up funds to D.G. We thank Dr. Martine Torres for her critical review and helpful comments of the manuscript. D.G. conceived the ideas. X.C. F.G. and D.G. designed the experiments. X.C. F.G. X.W. Y.Z. Z.T. C.C. and R.Z. performed the experiments. C.W. M.P. and X.H. conducted lipidomics. X.C. F.G. C.W. X.H. V.P. A.C. and D.G. analyzed the data. X.M. conducted biostatistics and bioinformatics analysis. C.H. provided TMA. X.C. and D.G. wrote the manuscript, and all authors reviewed and approved the manuscript for publication. The authors declare that there are no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = aug,
day = "4",
doi = "10.1016/j.cmet.2020.06.002",
language = "English (US)",
volume = "32",
pages = "229--242.e8",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "2",
}