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 longchain 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.
|Number of pages||10|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 2020 Dec 22|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank Dr. Kyung-Min Noh for providing the pSpCas9(BB)-2A-RFP plasmid. This study was supported by grants from the KRIBB Research Initiative Program, the Korea Basic Science Institute (C060200), the Development of Measurement Standards and Technology for Biomaterials and Medical Convergence funded by the Korea Research Institute of Standards and Science (KRISS–2020–GP2020-0004), and the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT and Future Planning (NRF-2015M3A9D7029882, NRF-2017M3A9G5083321, NRF-2017M3A9G5083322, 2019M3A9D5A01102796, NRF-2019R1C1C1002831, and NRF-2020R1A2C2007835).
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