Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America.
PLoS One. 2011;6(11):e28186. doi: 10.1371/journal.pone.0028186. Epub 2011 Nov 30.
Genes coding for the fatty acid desaturases (FADS1, 2, 3) localized at the cancer genomic hotspot 11q13 locus are required for the biosynthesis of 20 carbon polyunsaturated fatty acids (PUFA) that are direct eicosanoid precursors. In several cancer cell lines, FADS2 encoded Δ6 and Δ8 desaturation is not functional.
METHODOLOGY/PRINCIPAL FINDINGS: Analyzing MCF7 cell fatty acids with detailed structural mass spectrometry, we show that in the absence of FADS2 activity, the FADS1 product Δ5-desaturase operates to produce 5,11,14-20∶3 and 5,11,14,17-20∶4. These PUFA are missing the 8-9 double bond of the eicosanoid signaling precursors arachidonic acid (5,8,11,14-20∶4) and eicosapentaenoic acid (5,8,11,14,17-20∶5). Heterologous expression of FADS2 restores Δ6 and Δ8-desaturase activity and normal eicosanoid precursor synthesis.
CONCLUSIONS/SIGNIFICANCE: The loss of FADS2-encoded activities in cancer cells shuts down normal PUFA biosynthesis, deleting the endogenous supply of eicosanoid and downstream docosanoid precursors, and replacing them with unusual butylene-interrupted fatty acids. If recapitulated in vivo, the normal eicosanoid and docosanoid cell signaling milieu would be depleted and altered due to reduction and substitution of normal substrates with unusual substrates, with unpredictable consequences for cellular communication.
位于癌症基因组热点 11q13 位置的脂肪酸去饱和酶（FADS1、2、3）编码的基因是合成 20 碳多不饱和脂肪酸（PUFA）所必需的，20 碳多不饱和脂肪酸是直接类二十烷酸前体。在几种癌细胞系中，FADS2 编码的 Δ6 和 Δ8 去饱和作用没有功能。
方法/主要发现：用详细的结构质谱分析 MCF7 细胞脂肪酸，我们表明在缺乏 FADS2 活性的情况下，FADS1 产物 Δ5-去饱和酶起作用产生 5,11,14-20∶3 和 5,11,14,17-20∶4。这些 PUFA 缺少类二十烷酸信号前体花生四烯酸（5,8,11,14-20∶4）和二十碳五烯酸（5,8,11,14,17-20∶5）的 8-9 双键。FADS2 的异源表达恢复了 Δ6 和 Δ8-去饱和酶活性和正常的类二十烷酸前体合成。
结论/意义：癌细胞中 FADS2 编码活性的丧失阻止了正常的 PUFA 生物合成，消除了内源性类二十烷酸和下游二十二碳烷酸前体的供应，并以不寻常的丁烯中断脂肪酸取代它们。如果在体内得到重现，由于正常底物的减少和取代为不寻常的底物，正常的类二十烷酸和二十二碳烷酸细胞信号环境将被耗尽和改变，这对细胞通讯会产生不可预测的后果。
