Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer
Menée sur des cellules de cancer gastrique, cette étude met en évidence le rôle de la voie de la biosynthèse des acides gras poly-insaturés dans la sensibilité des cellules cancéreuses à la ferroptose
Résumé en anglais
Phosphatidylethanolamine (PE)-linked arachidonic acid (AA) and adrenic acid (AdA) are well-known substrates for lipid peroxidation, which are indispensable for ferroptosis, an iron-dependent regulated necrosis. However, how cells differentially regulate the intracellular pools of AA and AdA is not fully understood. Here, elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) are differentially expressed in gastric cancer cells, discriminating the cellular susceptibility to ferroptosis. Biochemical and lipidomics analyses support the hypothesis that ELOVL5 and FADS1 are required to maintain intracellular levels of AA and AdA and promote ferroptosis. Our study highlights the biosynthesis of AA and AdA by ELOVL5 and FADS1 as a critical checkpoint in the ferroptosis pathway.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.All study data are included in the article and supporting information.
