Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking

IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Kelly H. Sokol, Cameron J. Lee, Thomas J. Rogers, Althea Waldhart, Abigail E. Ellis, Sahithi Madireddy, Samuel R. Daniels, Rachel (Rae) J. House, Xinyu Ye, Mary Olesnavich, Amy Johnson, Benjamin R. Furness, Ryan D. Sheldon, Evan C. Lien
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引用次数: 0

Abstract

Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.

Abstract Image

脂质供应通过调节多不饱和脂肪酸的运输影响癌细胞对铁蛋白沉积的敏感性
铁中毒是由脂质过氧化引起的一种细胞死亡形式,正逐渐成为癌症治疗的靶点,这突出表明有必要确定影响铁中毒易感性的因素。脂质过氧化主要发生在含有多不饱和脂肪酸(PUFA)的磷脂上。在这里,我们发现即使细胞外脂质限制降低了细胞中的多不饱和脂肪酸水平,但缺脂的癌细胞却对铁中毒更为敏感。利用基于质谱的脂质组学和稳定同位素脂肪酸标记,我们发现脂质限制诱导脂肪酸贩运途径,其中 PUFA 从甘油三酯中释放出来,合成高度不饱和的 PUFA,如花生四烯酸和肾上腺酸。然后,这些 PUFAs 会在磷脂(包括醚磷脂)中积聚,从而促进铁变态反应的敏感性。因此,癌细胞内的 PUFA 含量并不一定与铁中毒敏感性相关。相反,癌细胞如何通过将 PUFA 转化为适当的磷脂池来对细胞外脂质水平做出反应,才会导致其对铁中毒的敏感性。
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来源期刊
Cell Chemical Biology
Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍: Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.
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