Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 34141 Daejeon, Korea.
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141 Daejeon, Korea.
Proc Natl Acad Sci U S A. 2020 Dec 22;117(51):32433-32442. doi: 10.1073/pnas.2006828117. Epub 2020 Dec 7.
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.
铁死亡是一种由脂质过氧化介导的铁依赖性调节性细胞坏死。癌细胞通过改变脂质代谢在代谢应激条件下存活，这可能改变它们对铁死亡的敏感性。然而，脂质代谢与铁死亡之间的关联尚不完全清楚。在本研究中，我们发现延伸超长链脂肪酸蛋白 5（ELOVL5）和脂肪酸去饱和酶 1（FADS1）的表达在间质型胃癌细胞（GCs）中上调，导致铁死亡敏感性增加。相比之下，这些酶在肠型 GCs 中被 DNA 甲基化沉默，使细胞对铁死亡产生抗性。脂质谱分析和同位素示踪分析表明，肠型 GCs 无法从亚油酸中生成花生四烯酸（AA）和花生五烯酸（AdA）。AA 补充到肠型 GCs 中可恢复其对铁死亡的敏感性。基于这些数据，多不饱和脂肪酸（PUFA）生物合成途径在铁死亡中起着至关重要的作用；因此，该途径可能代表预测铁死亡介导的癌症治疗效果的标志物。
