Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

Cited 15 time in scopus
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Title
Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer
Author(s)
Ji-Yoon Lee; M Nam; H Y Son; K Hyun; S Y Jang; Jong Woo Kim; Min Wook Kim; Y Jung; E Jang; S J Yoon; J Kim; J Kim; Jinho SeoJeong Ki MinKyoung-Jin OhBaek Soo HanWon Kon KimKwang-Hee Bae; J Song; J Kim; Y M Huh; G S Hwang; Eun-Woo LeeSang Chul Lee
Bibliographic Citation
Proceedings of National Academy of Sciences of United States of America, vol. 117, no. 51, pp. 32433-32442
Publication Year
2020
Abstract
Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.
Keyword
FerroptosisLipid peroxidationELOVL5FADS1Arachidonic acid
ISSN
0027-8424
Publisher
Natl Acad Sciences
DOI
http://dx.doi.org/10.1073/pnas.2006828117
Type
Article
Appears in Collections:
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Division of Research on National Challenges > Biodefense Research Center > 1. Journal Articles
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