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Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

Authors :
Seo Young Jang
Youngae Jung
Sang Chul Lee
Min Wook Kim
Eun-Woo Lee
Jung-Eun Kim
Jong Woo Kim
Jaewhan Song
Miso Nam
Jin-Ho Seo
Baek Soo Han
Jeong Ki Min
Kyoung Jin Oh
Geum-Sook Hwang
Kwang-Hee Bae
Ji Yoon Lee
Hye Young Son
Won Kon Kim
Seon Jin Yoon
Jihye Kim
Eunji Jang
Yong Min Huh
Jae-Hoon Kim
Kwangbeom Hyun
Source :
Proc Natl Acad Sci U S A
Publication Year :
2020
Publisher :
Proceedings of the National Academy of Sciences, 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.

Details

ISSN :
10916490 and 00278424
Volume :
117
Database :
OpenAIRE
Journal :
Proceedings of the National Academy of Sciences
Accession number :
edsair.doi.dedup.....ae785c2889135f51c9e6402e03dbff2f