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Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer
- 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.
- Subjects :
- Fatty Acid Desaturases
Fatty Acid Elongases
FADS1
Linoleic acid
Lipid peroxidation
chemistry.chemical_compound
Delta-5 Fatty Acid Desaturase
Stomach Neoplasms
Cell Line, Tumor
Ferroptosis
Humans
Promoter Regions, Genetic
Fatty Acid Desaturase 1
chemistry.chemical_classification
Arachidonic Acid
Multidisciplinary
Fatty acid
Lipid metabolism
DNA Methylation
Biological Sciences
Lipid Metabolism
Gene Expression Regulation, Neoplastic
Enhancer Elements, Genetic
chemistry
Biochemistry
Fatty Acids, Unsaturated
Arachidonic acid
Carbolines
Polyunsaturated fatty acid
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 117
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....ae785c2889135f51c9e6402e03dbff2f