Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects
Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects
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DOI：
10.1016/j.cmet.2021.05.016
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发表时间：
2021-08-03
期刊：
影响因子：
29
通讯作者：
Feron, Olivier
中科院分区：
文献类型：
--
作者：
Dierge, Emeline;Debock, Elena;Feron, Olivier
肿瘤酸中毒通过刺激癌细胞中的脂肪酸（FA）代谢来促进疾病进展。我们没有阻止酸性癌细胞对 FA 的使用，而是研究了特定 FA 的过量摄取是否会导致抗肿瘤作用。我们发现，在环境酸中毒下，n-3 以及 n-6 多不饱和 FA (PUFA) 选择性诱导癌细胞铁死亡。当超过甘油三酯储存到脂滴中的缓冲能力时，n-3和n-6 PUFA过氧化会导致与双键数量成比例的细胞毒性作用，并且在二酰基甘油酰基转移酶抑制剂（DGATi）存在的情况下更是如此。最后，与富含单不饱和 FA 的饮食相比，富含 n-3 长链 PUFA 的饮食显着延迟了小鼠肿瘤的生长，通过给予 DGATi 或铁死亡诱导剂进一步增强了这种效果。这些数据指出膳食多不饱和脂肪酸作为一种选择性辅助抗肿瘤方式，可以有效补充药理学方法。
Tumor acidosis promotes disease progression through a stimulation of fatty acid (FA) metabolism in cancer cells. Instead of blocking the use of FAs by acidic cancer cells, we examined whether excess uptake of specific FAs could lead to antitumor effects. We found that n-3 but also remarkably n-6 polyunsaturated FA (PUFA) selectively induced ferroptosis in cancer cells under ambient acidosis. Upon exceeding buffering capacity of triglyceride storage into lipid droplets, n-3 and n-6 PUFA peroxidation led to cytotoxic effects in proportion to the number of double bonds and even more so in the presence of diacylglycerol acyltransferase inhibitors (DGATi). Finally, an n-3 long-chain PUFA-rich diet significantly delayed mouse tumor growth when compared with a monounsaturated FA-rich diet, an effect further accentuated by administration of DGATi or ferroptosis inducers. These data point out dietary PUFA as a selective adjuvant antitumor modality that may efficiently complement pharmacological approaches.