Apocryphal FADS2 activity promotes fatty acid diversification in cancer
Apocryphal FADS2 activity promotes fatty acid diversification in cancer
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DOI：
10.1016/j.celrep.2021.108738
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发表时间：
2021-02-09
期刊：
影响因子：
8.8
通讯作者：
Blanksby, Stephen J.
中科院分区：
文献类型：
--
作者：
Young, Reuben S. E.;Bowman, Andrew P.;Blanksby, Stephen J.
典型脂肪酸代谢描述了特定的酶-底物相互作用，其导致具有明确定义的链长、程度和不饱和位置的产物。在一系列前列腺癌细胞系中对脂质的深度分析揭示了具有不寻常的不饱和位点的多种脂肪酸，这些位点未被经典途径描述。这些不寻常的脂质的结构和丰度与去饱和酶表达的变化相关，并且是细胞表型的强指标。基因沉默和稳定同位素示踪表明，FADS 2直接使14：0（肉豆蔻酸）、16：0（棕榈酸）和18：0（硬脂酸）的Delta 6和Delta 8去饱和，产生了新的不饱和脂肪酸家族（包括n-8、n-10和n-12），这些家族在人源性细胞中很少报告。异构体分辨脂质组学揭示了这些不寻常的脂肪酸选择性地掺入到复杂的结构脂质中，并确定了它们在癌组织中的存在，表明在膜结构和信号传导中的功能作用。
Canonical fatty acid metabolism describes specific enzyme-substrate interactions that result in products with well-defined chain lengths, degree(s), and positions of unsaturation. Deep profiling of lipids across a range of prostate cancer cell lines reveals a variety of fatty acids with unusual site(s) of unsaturation that are not described by canonical pathways. The structure and abundance of these unusual lipids correlate with changes in desaturase expression and are strong indicators of cellular phenotype. Gene silencing and stable isotope tracing demonstrate that direct Delta 6 and Delta 8 desaturation of 14:0 (myristic), 16:0 (palmitic), and 18:0 (stearic) acids by FADS2 generate new families of unsaturated fatty acids (including n-8, n-10, and n-12) that have rarely-if ever-been reported in human-derived cells. Isomer-resolved lipidomics reveals the selective incorporation of these unusual fatty acids into complex structural lipids and identifies their presence in cancer tissues, indicating functional roles in membrane structure and signaling.