FADS2 Function Loss at the Cancer Hotspot 11q13 Locus Diverts Lipid Signaling Precursor Synthesis to Unusual Eicosanoid Fatty Acids

Abstract

BackgroundGenes 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 FindingsAnalyzing 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/SignificanceThe 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.

Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis

“…In humans, membrane-bound PUFA desaturases known as “front-end” desaturases introduce a nascent double bond between an existing double bond usually located between the carboxyl group and the 9 th carbon atoms from the terminal methyl (n-9) [5]. Front-end desaturation proceeds at the Δ4, Δ5, Δ6 and Δ8 positions and is responsible for endogenous biosynthesis of LCPUFA [3, 6, 7]. …”

“…It introduces a double bond at the Δ5 position (between carbons 5-6) by acting on at least four 20-carbon fatty acid substrates 20:3n-3, 20:4n-3, 20:2n-6 and 20:3n-6 [6]. When FADS2 is absent, FADS1 produces rare butylene-interrupted fatty acids, for instance 5,11,14-20:3 and 5,11,14,17-20:4.…”

Fads1 and 2 are promoted to meet instant need for long-chain polyunsaturated fatty acids in goose fatty liver

“…A cross-sectional study also shows that Fads genotype is an important determinant of docosahexaenoic acid (DHA) status in Danish infants [30]. Moreover, data from genome-wide association study and gene expression profiling as well as functional studies indicate that Fads1 is associated with cholesterol level and coronary artery disease [31], insulin resistance [32], and breast cancer [33], while Fads2 is associated with conditional change of skin, reproductive systems, and intestine [34,35], infant intelligence quotient [36], attention-deficit/hyperactivity disorder [37], breast cancer [33], and statin sensitivity [38]. Recently, Fads genes and their variants have been associated with multiple metabolic phenotypes in humans, that is, three Fads SNPs are not only associated with decreased hepatic expression of Fads1, but also associated with increased total hepatic fat content [39].…”

Influence of the cis-9, cis-12 and cis-15 double bond position in octadecenoic acid (18:1) isomers on the rat FADS2-catalyzed Δ6-desaturation

“…FA substrate FA product References 6-desaturase cis9-16:1 (palmitoleic acid, 16:1 n-7) cis6,cis9-16:2 (16:2 n-7) Brenner, 1971 cis9-18:1 (oleic acid, 18:1 n-9) cis6,cis9-18:2 (18:2 n-9) Brenner, 1971 cis9,cis12-18:2 (linoleic acid, 18:2 n-6) cis6,cis9,cis12-18:3 (-linolenic acid, 18:3 n-6) Brenner, 1971 cis9,cis12,cis15-18:3 (-linolenic acid, 18:3 n-3) cis6,cis9,cis12,cis15-18:4 (stearidonic acid, 18:4 n-3) Brenner, 1971 cis9,cis12,cis15,cis18-24:4 (24:4 n-6) , 1997;Banni et al, 2001trans10,cis12-18:2 cis6,trans10,cis12-18:3 Sébédio et al, 2001 cis8,cis11,cis14-20:3 (dihomo-linolenic acid acid, 20:3 n-6) Park et al, 2009;Park et al, 2011 cis11,cis14,cis17-20:3 (11,14,17-eicosatrienoic acid, 20:3 n-3) cis8, cis11,cis14,cis17-20:2 (8,11,14,17-eicosatetraenoic acid, 20:4 n-3) Park et al, 2009;Park et al, 2011 …”

“…Next, evidence that FADS2 also catalyzes the 8-desaturation for both 20:2 n-6 and 20:3 n-3 was described, representing an alternative pathway for the synthesis of cellular 20:3 n-6 and 20:4 n-3 (Park et al, 2009;Park et al, 2011). Finally, FADS2 was shown to 6-desaturate rumenic acid, the cis9,trans11-conjugated linoleic acid (CLA) (Sebedio et al, 1997;Banni et al, 2001), its trans10,cis12-CLA isomer (Sébédio et al, 2001) and trans-vaccenic acid .…”